Plasma compositions and methods of use thereof

ABSTRACT

Provided herein are pathogen-inactivated plasma compositions and methods for treating a disease or condition using pathogen-inactivated plasma compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. ProvisionalApplication Ser. No. 62/245,926, filed Oct. 23, 2015; 62/268,462, filedDec. 16, 2015; and 62/354,653, filed Jun. 24, 2016; each of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The methods described herein generally relate to the preparation and useof plasma compositions. More particularly, the present disclosurerelates to pathogen-inactivated plasma compositions and their use inimproved treatment methods using such compositions for therapeuticplasma exchange or infusion.

BACKGROUND

Blood collection and processing serves a critical role in healthcareworldwide, and millions of units of donated whole blood are collected byblood banks each year. While some whole blood units collected fromdonors are stored and used for transfusion, most whole blood is insteadseparated into its clinically therapeutic components of red blood cells,platelets and plasma, for individual storage and use in treatingdifferent medical needs and conditions requiring one or more of theparticular blood components. Additionally, other blood derived productsmay be produced through fractionation procedures, such as for example,intravenous immunoglobulin G (IVIG), a product obtained by fractionationof human plasma (Radosevich et al., 2010, Vox Sanguinis, 98: 12-28).

Cryoprecipitate (also known as “cryo”) is a blood product comprising aportion of plasma rich in coagulation factors. Cyroprecipitate, alsoreferred to as cryoprecipitated antihaemophilic factor (AHF),cryoprecipitated AHF, is prepared by slow, controlled thawing of frozenplasma (e.g., whole blood-derived fresh frozen plasma, or FFP), forexample between 1° and 6° C. (e.g., 4±2° C.), which results in theformation of a white precipitate, and then recovering the precipitatefollowing separation from the remaining liquid plasma portion, such asby refrigerated centrifugation. The remaining liquid plasma portion,also referred to herein as “supernatant” and various other terminology,such as “cryo-poor plasma” (CPP), “cryosupernatant”,“cryoprecipitate-reduced plasma”, or “cryo-reduced plasma”, is removedfrom the cryoprecipitate bag and the isolated cold-insoluble precipitateis re-suspended in a portion of the plasma (e.g., the cryo-poor plasma)left behind and generally re-frozen within 1 hour, and stored frozenuntil needed for transfusion. The cryo-poor plasma contains plasmaproteins not partitioned with the cryoprecipitate and generally is usedfor plasma fractionation to produce various components (e.g., plasmafactors), as well as for certain, very limited therapeutic applications.

Cryoprecipitate serves as a source of fibrinogen, Factor VIII, FactorXIII, vWF, and fibronectin. This component is used in the control ofbleeding associated with fibrinogen deficiency and to treat Factor XIIIdeficiency when volume considerations preclude the use of frozen plasmaand recombinant proteins are not available. It is also indicated assecond-line therapy for von Willebrand disease and hemophilia A (FactorVIII deficiency).

In addition to the primary use of plasma in transfusions to correctdeficiencies of clotting factors or coagulopathy in patients with activebleeding, such as for example surgery and trauma, plasma (e.g., FFP) andplasma derived components (e.g., IVIG) may be used for treatment ofvarious diseases or conditions. For example, immunotherapy usingtherapeutic plasma exchange (TPE) or intravenous immunoglobulin (IVIG)or a combination of both has been used for treatment of a variety ofdiseases or conditions. Many such the diseases or conditions have beencategorized by the American Society for Apheresis (ASFA) based onliterature guidance. TPE is a therapeutic procedure using bulk removalof plasma from patients. In a TPE process, blood is removed andseparated into plasma and cellular components (e.g., platelets, redblood cells), followed by mixing of the cellular components with someform of replacement fluid, and reinfusion into the patient (Winters,2012, Hematology ASH Education Book 2012:7-12). TPE removes pathologicsubstances such as pathologic antibodies (e.g., autoantibodies), immunecomplexes, and cytokines, and may have additional immunomodulatoryeffects. Because TPE involves the bulk removal of plasma, anythingcirculating in the plasma will be removed, leading to a temporarydecline in normal plasma components such as factor V, factor VII, factorVIII, factor IX, factor X, VWF and fibrinogen. Depending on the medicalindication, plasma that is removed can be replaced with human albumin(e.g., 4%-5% in physiologic saline) which is relatively common, oralternatively additional plasma (e.g., fresh frozen plasma, FFP), oreven the patient's own plasma after a secondary purification procedure(Ward, 2011, J. Clin. Apheresis 26:230-238).

There remains a need for improved compositions and methods for treatmentof various diseases and conditions through the use of therapeutic plasmaexchange or infusion.

SUMMARY

The pathogen-inactivated plasma compositions and methods describedherein are useful for the treatment of various diseases or conditions,including, for example, in providing improved treatment methods usingsuch plasma compositions for therapeutic plasma exchange or infusion.

In one aspect, the present disclosure provides a composition comprisinga cryoprecipitate suitable for infusion into a subject at least 1 dayafter thawing, wherein the cryoprecipitate is pathogen-inactivated. Insome embodiments, the composition is suitable for infusion into asubject at least 3 days after thawing. In some embodiments, thecomposition is suitable for infusion into a subject at least 5 daysafter thawing. In some embodiments, the composition is suitable forinfusion into a subject at least 7 days after thawing. In someembodiments, the composition comprises less than 80 IU of factor VIIIper unit of cryoprecipitate. In some embodiments, the compositioncomprises less than 50 IU of factor VIII per unit of cryoprecipitate. Insome embodiments, the composition comprises at least 150 mg offibrinogen per unit of cryoprecipitate. In some embodiments, thecomposition further comprises plasma of a volume between about 15 mL andabout 20 mL. In some embodiments, the composition comprisescryoprecipitate obtained from about 600 mL of pathogen-inactivatedplasma. In some embodiments, the composition comprises a firstcryoprecipitate obtained from about 600 mL of pathogen-inactivatedplasma and a second cryoprecipitate obtained from about 600 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to re-freezing for storage. In someembodiments, the composition comprises cryoprecipitate obtained from atleast about 600 mL and less than 650 mL of pathogen-inactivated plasma.In some embodiments, the composition comprises a first cryoprecipitateobtained from at least about 600 mL and less than 650 mL ofpathogen-inactivated plasma and a second cryoprecipitate obtained fromat least about 600 mL and less than 650 mL of pathogen-inactivatedplasma, wherein the first and the second cryoprecipitates are combinedprior to re-freezing for storage. In some embodiments, the compositionfurther comprises plasma of a volume between about 50 mL and about 60mL. In some embodiments, the composition is stored at room temperaturefor the at least 1 day after thawing. In some embodiments, thecryoprecipitate has been pathogen-inactivated by photochemicalinactivation. In some embodiments, the cryoprecipitate has beenpathogen-inactivated by photoinactivation with psoralen. In someembodiments, the psoralen is amotosalen.

In another aspect, the present disclosure provides a method of preparinga cryoprecipitate for infusion into a subject comprising a) preparing acryoprecipitate from pathogen-inactivated plasma; b) freezing thecryoprecipitate; and c) thawing the frozen cryoprecipitate, wherein theresulting cryoprecipitate of step c) is suitable for infusion into asubject at least 1 day after thawing. In some embodiments, the methodfurther comprises testing the thawed cryoprecipitate for fibrinogen. Insome embodiments, the method does not comprise testing the thawedcryoprecipitate for factor VIII. In some embodiments, thecryoprecipitate is prepared from about 600 mL of pathogen-inactivatedplasma. In some embodiments, the method further comprises combining afirst cryoprecipitate prepared from about 600 mL of pathogen-inactivatedplasma and a second cryoprecipitate prepared from about 600 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to steps b) and c). In someembodiments, the cryoprecipitate is prepared from at least about 600 mLand less than 650 mL of pathogen-inactivated plasma. In someembodiments, the method further comprises combining a firstcryoprecipitate prepared from at least about 600 mL and less than 650 mLof pathogen-inactivated plasma and a second cryoprecipitate preparedfrom at least about 600 mL and less than 650 mL of pathogen-inactivatedplasma, wherein the first and the second cryoprecipitates are combinedprior to steps b) and c). In some embodiments, the resultingcryoprecipitate of step c) is suitable for infusion into a subject atleast 3 days after thawing. In some embodiments, the resultingcryoprecipitate of step c) is suitable for infusion into a subject atleast 5 days after thawing. In some embodiments, the resultingcryoprecipitate of step c) is suitable for infusion into a subject atleast 7 days after thawing.

In yet another aspect, the present disclosure provides a method ofinfusing a cryoprecipitate into a subject comprising a) preparing acryoprecipitate from pathogen-inactivated plasma; b) freezing thecryoprecipitate; c) thawing the frozen cryoprecipitate; and d) infusingthe thawed cryoprecipitate into a subject, wherein the infusion occursat least 1 day after thawing the frozen cryoprecipitate. In someembodiments, the method further comprises testing the thawedcryoprecipitate for fibrinogen. In some embodiments, the method does notcomprise testing the thawed cryoprecipitate for factor VIII beforetransfusing the thawed cryoprecipitate. In some embodiments, thecryoprecipitate is prepared from about 600 mL of pathogen-inactivatedplasma. In some embodiments, the method further comprises combining afirst cryoprecipitate prepared from about 600 mL of pathogen-inactivatedplasma and a second cryoprecipitate prepared from about 600 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to step b). In some embodiments, thecryoprecipitate is prepared from at least about 600 mL and less than 650mL of pathogen-inactivated plasma. In some embodiments, the methodfurther comprises combining a first cryoprecipitate prepared from atleast about 600 mL and less than 650 mL of pathogen-inactivated plasmaand a second cryoprecipitate prepared from at least about 600 mL andless than 650 mL of pathogen-inactivated plasma, wherein the first andthe second cryoprecipitates are combined prior to step b).

In some embodiments of any of the above embodiments, the resultingcryoprecipitate of step c) comprises less than 80 IU of factor VIII perunit of cryoprecipitate. In some embodiments, the resultingcryoprecipitate of step c) comprises less than 50 IU of factor VIII perunit of cryoprecipitate. In some embodiments of any of the aboveembodiments, the resulting cryoprecipitate of step c) comprises at least150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments,the cryoprecipitate of step a) further comprises plasma of a volumebetween about 15 mL and about 20 mL. In some embodiments, thecryoprecipitate of step a) further comprises plasma of a volume betweenabout 50 mL and about 60 mL. In some embodiments of any of the aboveembodiments, the plasma has been pathogen-inactivated by photochemicalinactivation. In some embodiments, the cryoprecipitate has beenpathogen-inactivated by photoinactivation with psoralen. In someembodiments, the psoralen is amotosalen. In some embodiments of any ofthe above embodiments, the subject is a human.

In still another aspect, the present disclosure provides a kitcomprising a) a container; b) a pathogen-inactivated cryoprecipitate;and c) instructions for using the pathogen-inactivated cryoprecipitatein an infusion into a subject, wherein the instructions indicate thatthe cryoprecipitate is suitable for infusion into the subject for up toabout 5 days after thawing.

In still another aspect, the present disclosure provides a method ofinfusing a cryoprecipitate into a subject, comprising infusing into thesubject the composition of any of the above embodiments.

In still another aspect, the present disclosure provides a methodinfusing a cryoprecipitate into a subject, comprising infusing into thesubject a cryoprecipitate produced by the method of any of the aboveembodiments.

In still another aspect, the present disclosure provides acryoprecipitate produced by the method of any of the above embodiments.

In still another aspect, the present disclosure provides a compositioncomprising a cryoprecipitate suitable for infusion into a subject atleast 1 day after thawing, wherein the cryoprecipitate ispathogen-inactivated. In some embodiments, the composition is suitablefor infusion into a subject at least 3 days after thawing. In someembodiments, the composition is suitable for infusion into a subject atleast 5 days after thawing. In some embodiments, the compositioncomprises cryoprecipitate prepared from at least about 550 mL and lessthan about 650 mL of pathogen-inactivated plasma. In some embodiments,the composition comprises cryoprecipitate prepared from about 600 mL ofpathogen-inactivated plasma. In some embodiments, the compositioncomprises cryoprecipitate prepared from 3 units of pathogen-inactivatedplasma. In some embodiments, the composition comprises a firstcryoprecipitate prepared from at least about 550 mL and less than 650 mLof pathogen-inactivated plasma and a second cryoprecipitate preparedfrom at least about 550 mL and less than 650 mL of pathogen-inactivatedplasma, wherein the first and the second cryoprecipitates are combinedprior to re-freezing for storage. In some embodiments, the compositioncomprises a first cryoprecipitate prepared from about 600 mL ofpathogen-inactivated plasma and a second cryoprecipitate prepared fromabout 600 mL of pathogen-inactivated plasma, wherein the first and thesecond cryoprecipitates are combined prior to re-freezing for storage.In some embodiments, the composition comprises a first cryprecipitateprepared from 3 units of pathogen-inactivated plasma and a secondcryoprecipitate prepared from 3 units of pathogen-inactivated plasma,wherein the first and the second cryoprecipitates are combined prior tore-freezing for storage. In some embodiments, the composition comprisescryoprecipitate prepared from 6 units of pathogen-inactivated plasma. Insome embodiments, the composition comprises cryoprecipitate preparedfrom plasma obtained from one donor. In some embodiments, thecomposition comprises cryoprecipitate prepared from plasma obtained from2-6 donors. In some embodiments, the composition comprises less than 80IU of factor VIII per unit of cryoprecipitate. In some embodiments, thecomposition comprises less than 50 IU of factor VIII per unit ofcryoprecipitate. In some embodiments, the composition comprises 80-100IU of factor VIII per unit of cryoprecipitate. In some embodiments, thecomposition comprises at least 80 IU of factor VIII. In someembodiments, the composition comprises 80-240 IU of factor VIII. In someembodiments, the composition comprises 80-480 IU of factor VIII. In someembodiments, the amount of factor VIII is determined fromcryoprecipitate sampled within about 2 hours after thawing. In someembodiments, the amount of factor VIII is determined fromcryoprecipitate sampled about 1 day after thawing. In some embodiments,the amount of factor VIII is determined from cryoprecipitate sampledabout 3 days after thawing. In some embodiments, the amount of factorVIII is determined from cryoprecipitate sampled about 5 days afterthawing. In some embodiments, the composition comprises at least 150 mgof fibrinogen per unit of cryoprecipitate. In some embodiments, thecomposition comprises at least 250 mg of fibrinogen per unit ofcryoprecipitate. In some embodiments, the composition comprises at least750 mg of fibrinogen. In some embodiments, the composition comprises atleast 1500 mg of fibrinogen. In some embodiments, each unit ofcryoprecipitate is prepared from 180-250 mL of pathogen-inactivatedplasma. In some embodiments, the composition further comprises plasma ofa volume between about 5 mL and about 20 mL per unit of cryoprecipitate.In some embodiments, the composition further comprises plasma of avolume greater than about 1 mL and less than or equal to about 75 mL. Insome embodiments, the composition further comprises plasma of a volumebetween about 50 mL and about 60 mL. In some embodiments, thecomposition further comprises plasma of a volume between about 30 mL andabout 120 mL. In some embodiments, the composition is stored at roomtemperature for at least 1 day after thawing. In some embodiments, thecomposition is stored at between about 2° C. and about 6° C. for atleast 1 day after thawing. In some embodiments, the cryoprecipitate hasbeen pathogen-inactivated by photochemical inactivation. In someembodiments, the cryoprecipitate has been pathogen-inactivated byphotochemical inactivation with a psoralen. In some embodiments, thepsoralen is amotosalen. In some embodiments, the cryoprecipitate isprepared from plasma that has been pathogen-inactivated in a firstcontainer suitable for photochemical inactivation of the plasma understerile conditions; wherein the first container is coupled to a compoundabsorption device (CAD) such that the pathogen-inactivated plasma can betransferred from the first container to the CAD under sterileconditions; and wherein the cryoprecipitate is contained within one ormore second containers, each of which is coupled to the CAD such thatthe pathogen-inactivated plasma can be transferred from the CAD to theone or more second containers under sterile conditions, and each ofwhich is suitable for freezing the pathogen-inactivated plasma followedby thawing of the pathogen-inactivated plasma under conditions thatprovide for the formation of the cryoprecipitate. In some embodiments,each of the one or more second containers is suitable for freezing thepathogen-inactivated plasma, followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of the cryoprecipitate and a cryosupernatant, followed byremoval of all or a portion of the cryosupernatant from the one or moresecond containers. In some embodiments, the cryoprecipitate is preparedfrom plasma that has been pathogen-inactivated in a first containersuitable for photochemical inactivation of the plasma under sterileconditions; wherein the first container is coupled to a compoundabsorption device (CAD) such that the pathogen-inactivated plasma can betransferred from the first container to the CAD under sterileconditions; wherein the CAD is coupled to one or more second containers,each of which is coupled to the CAD such that the pathogen-inactivatedplasma can be transferred from the CAD to the one or more secondcontainers under sterile conditions; and wherein the cryoprecipitate iscontained within a third container configured to be coupled to one ormore second containers, such that the pathogen-inactivated plasma can betransferred from the CAD to the one or more second containers to thethird container under sterile conditions, wherein the third container issuitable for freezing the pathogen-inactivated plasma followed bythawing of the pathogen-inactivated plasma under conditions that providefor the formation of the cryoprecipitate. In some embodiments, the thirdcontainer is suitable for freezing the pathogen-inactivated plasma,followed by thawing of the pathogen-inactivated plasma under conditionsthat provide for the formation of the cryoprecipitate and acryosupernatant, followed by removal of all or a portion of thecryosupernatant from the third container. In some embodiments, thecomposition is contained within a container that further comprises alabel indicating that the composition is suitable for use for at leastabout 1 day after thawing. In some embodiments, the composition iscontained within a container that further comprises a label indicatingthat the composition is suitable for use for at least about 3 days afterthawing. In some embodiments, the composition is contained within acontainer that further comprises a label indicating that the compositionis suitable for use for at least about 5 days after thawing. In someembodiments, the cryoprecipitate is prepared from plasma other thangroup O plasma.

In still another aspect, the present disclosure provides a method ofpreparing a cryoprecipitate for infusion into a subject comprising: a)preparing a cryoprecipitate from pathogen-inactivated plasma; b)freezing the cryoprecipitate; and c) thawing the frozen cryoprecipitate,wherein the resulting cryoprecipitate of step c) is suitable forinfusion into a subject at least 1 day after thawing. In someembodiments, the thawed cryoprecipitate comprises at least about 150 mgof fibrinogen per unit of cryoprecipitate. In some embodiments, thethawed cryoprecipitate comprises at least about 750 mg of fibrinogen. Insome embodiments, the method does not comprise determining the level offactor VIII before infusing the thawed cryoprecipitate. In someembodiments, the method further comprises determining the level offactor VIII in the thawed cryoprecipitate. In some embodiments, thecryoprecipitate is prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma. In some embodiments, thecryoprecipitate is prepared from about 600 mL of pathogen-inactivatedplasma. In some embodiments, the method further comprises combining afirst cryoprecipitate prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma and a second cryoprecipitateprepared from at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to steps b) and c). In someembodiments, the method further comprises combining a firstcryoprecipitate prepared from about 600 mL of pathogen-inactivatedplasma and a second cryoprecipitate prepared from about 600 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to steps b) and c). In someembodiments, the method further comprises combining a firstcryprecipitate prepared from 3 units of pathogen-inactivated plasma anda second cryoprecipitate prepared from 3 units of pathogen-inactivatedplasma, wherein the first and the second cryoprecipitates are combinedprior to steps b) and c). In some embodiments, the resultingcryoprecipitate of step c) is suitable for infusion into a subject atleast 3 days after thawing. In some embodiments, the resultingcryoprecipitate of step c) is suitable for infusion into a subject atleast 5 days after thawing. In another aspect, provided herein is amethod of infusing a cryoprecipitate into a subject comprising: a)preparing a cryoprecipitate from pathogen-inactivated plasma; b)freezing the cryoprecipitate; c) thawing the frozen cryoprecipitate; andd) infusing the thawed cryoprecipitate into a subject, wherein theinfusion occurs at least 1 day after thawing the frozen cryoprecipitate.In some embodiments, the thawed cryoprecipitate comprises at least about150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments,the thawed cryoprecipitate comprises at least about 750 mg offibrinogen. In some embodiments, the method does not comprisedetermining the level of factor VIII before infusing the thawedcryoprecipitate. In some embodiments, the method further comprisesdetermining the level of factor VIII in the thawed cryoprecipitatebefore infusing the thawed cryoprecipitate. In some embodiments, thecryoprecipitate is prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma. In some embodiments, thecryoprecipitate is prepared from about 600 mL of pathogen-inactivatedplasma. In some embodiments, the method further comprises combining afirst cryoprecipitate prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma and a second cryoprecipitateprepared from at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to steps b) and c). In someembodiments, the method further comprises combining a firstcryoprecipitate prepared from about 600 mL of pathogen-inactivatedplasma and a second cryoprecipitate prepared from about 600 mL ofpathogen-inactivated plasma, wherein the first and the secondcryoprecipitates are combined prior to steps b) and c). In someembodiments, the method further comprises combining a firstcryprecipitate prepared from 3 units of pathogen-inactivated plasma anda second cryoprecipitate prepared from 3 units of pathogen-inactivatedplasma, wherein the first and the second cryoprecipitates are combinedprior to steps b) and c). In some embodiments, the resultingcryoprecipitate of step c) comprises less than 80 IU of factor VIII perunit of cryoprecipitate. In some embodiments, the resultingcryoprecipitate of step c) comprises at least about 80 IU of factorVIII. In some embodiments, the resulting cryoprecipitate of step c)comprises less than 50 IU of factor VIII per unit of cryoprecipitate. Insome embodiments of any of the above embodiments, the resultingcryoprecipitate of step c) comprises at least 150 mg of fibrinogen perunit of cryoprecipitate. In some embodiments of any of the aboveembodiments, the resulting cryoprecipitate of step c) comprises at least750 mg of fibrinogen. In some embodiments of any of the aboveembodiments, the cryoprecipitate of step a) further comprises plasma ofa volume between about 5 mL and about 20 mL per unit of cryoprecipitate.In some embodiments, the cryoprecipitate of step a) further comprisesplasma of a volume greater than about 1 mL and less than or equal toabout 75 mL. In some embodiments, the cryoprecipitate of step a) furthercomprises plasma of a volume between about 50 mL and about 60 mL. Insome embodiments, the cryoprecipitate of step a) further comprisesplasma of a volume between about 30 mL and about 120 mL. In someembodiments of any of the above embodiments, the plasma has beenpathogen-inactivated by photochemical inactivation. In some embodiments,the cryoprecipitate has been pathogen-inactivated by photochemicalinactivation with a psoralen. In some embodiments, the psoralen isamotosalen. In some embodiments of any of the above embodiments, thecryoprecipitate is prepared from plasma that has beenpathogen-inactivated in a first container suitable for photochemicalinactivation of the plasma under sterile conditions; wherein the firstcontainer is coupled to a compound absorption device (CAD) such that thepathogen-inactivated plasma can be transferred from the first containerto the CAD under sterile conditions; and wherein the cryoprecipitate isfrozen and thawed in steps b) and c) within one or more secondcontainers, each of which is coupled to the CAD such that thepathogen-inactivated plasma can be transferred from the CAD to the oneor more second containers under sterile conditions, and each of which issuitable for freezing the pathogen-inactivated plasma followed bythawing of the pathogen-inactivated plasma under conditions that providefor the formation of the cryoprecipitate. In some embodiments, each ofthe one or more second containers is suitable for freezing thepathogen-inactivated plasma, followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of the cryoprecipitate and a cryosupernatant, followed byremoval of all or a portion of the cryosupernatant from the one or moresecond containers. In some embodiments, the cryoprecipitate is preparedfrom plasma that has been pathogen-inactivated in a first containersuitable for photochemical inactivation of the plasma under sterileconditions; wherein the first container is coupled to a compoundabsorption device (CAD) such that the pathogen-inactivated plasma can betransferred from the first container to the CAD under sterileconditions; and wherein the cryoprecipitate is frozen and thawed insteps b) and c) within a third container configured to be coupled to oneor more second containers, such that the pathogen-inactivated plasma canbe transferred from the CAD to the one or more second containers to thethird container under sterile conditions, wherein the third container issuitable for freezing the pathogen-inactivated plasma followed bythawing of the pathogen-inactivated plasma under conditions that providefor the formation of the cryoprecipitate. In some embodiments, the thirdcontainer is suitable for freezing the pathogen-inactivated plasma,followed by thawing of the pathogen-inactivated plasma under conditionsthat provide for the formation of the cryoprecipitate and acryosupernatant, followed by removal of all or a portion of thecryosupernatant from the third container. In some embodiments of any ofthe above embodiments, the subject is a human.

In still another aspect, the present disclosure provides a kitcomprising: a) a container; b) a pathogen-inactivated cryoprecipitate;and c) instructions for using the pathogen-inactivated cryoprecipitatein an infusion into a subject, wherein the instructions indicate thatthe cryoprecipitate is suitable for infusion into the subject for up toabout 5 days after thawing.

In still another aspect, the present disclosure provides a kitcomprising: a) a container; b) a pathogen-inactivated cryoprecipitate;and c) a label indicating that the pathogen-inactivated cryoprecipitateis suitable for use for up to about 5 days after thawing.

In still another aspect, the present disclosure provides a method ofinfusing a cryoprecipitate into a subject, comprising infusing into thesubject the composition of any of the above embodiments.

In still another aspect, the present disclosure provides a method ofinfusing a cryoprecipitate into a subject, comprising infusing into thesubject a cryoprecipitate produced by any of the above embodiments.

In still another aspect, the present disclosure provides acryoprecipitate produced by any of the above embodiments.

In still another aspect, the present disclosure provides a method ofpreparing a pooled cryosupernatant for infusion into a subjectcomprising: a) freezing at least a first pathogen-inactivated plasma anda second pathogen-inactivated plasma, wherein the first and the secondpathogen-inactivated plasmas each have a volume of at least about 550 mLand less than about 650 mL; b) thawing the first pathogen-inactivatedplasma under conditions that provide for the formation of a firstprecipitate and a first supernatant, and thawing the secondpathogen-inactivated plasma under conditions that provide for theformation of a second precipitate and a second supernatant; c)separating the first and the second supernatants from the first and thesecond precipitates to form a first cryosupernatant and a secondcryosupernatant; and d) combining the first and the secondcryosupernatants to form a pooled cryosupernatant. In some embodiments,the first and the second pathogen-inactivated plasmas each have a volumeof about 600 mL. In some embodiments, step a) further comprises freezingat least a third pathogen-inactivated plasma and a fourthpathogen-inactivated plasma, wherein the third and the fourthpathogen-inactivated plasmas each have a volume of at least about 550 mLand less than 650 mL; step b) further comprises thawing the thirdpathogen-inactivated plasma under conditions that provide for theformation of a third precipitate and a third supernatant, and thawingthe fourth pathogen-inactivated plasma under conditions that provide forthe formation of a fourth precipitate and a fourth supernatant; step c)further comprises separating the third and the fourth supernatants fromthe third and the fourth precipitates to form a third cryosupernatantand a fourth cryosupernatant; the pooled cryosupernatant formed in stepd) is a first pooled supernatant, and step d) further comprisescombining the third and the fourth cryosupernatants to form a secondpooled cryosupernatant; and the method further comprises e) combiningthe first pooled cryosupernatant and the second pooled cryosupernatant.In some embodiments, the third and the fourth pathogen-inactivatedplasmas each have a volume of about 600 mL. In some embodiments, thefirst and/or the second pathogen-inactivated plasma have beenpathogen-inactivated by photochemical inactivation. In some embodiments,the one or more of the first, second, third, and fourthpathogen-inactivated plasmas have been pathogen-inactivated with apsoralen. In some embodiments, the psoralen is amotosalen. In someembodiments, one or more of the first, second, third, and fourthpathogen-inactivated plasmas have been pathogen-inactivated in a firstcontainer suitable for photochemical inactivation of plasma understerile conditions, wherein the first container is coupled to a compoundabsorption device (CAD) such that the pathogen-inactivated plasma can betransferred from the first container to the CAD under sterileconditions. In some embodiments, one or more of the first, second,third, and fourth pathogen-inactivated plasmas is frozen in step a) andthawed in step b) within one or more second containers, each of which iscoupled to the CAD such that the pathogen-inactivated plasma can betransferred from the CAD to the one or more second containers understerile conditions, and each of which is suitable for freezing thepathogen-inactivated plasma followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of the cryoprecipitate. In some embodiments, one or more ofthe first, second, third, and fourth pathogen-inactivated plasmas isfrozen in step a) and thawed in step b) within a third containerconfigured to be coupled to the one or more second containers, such thatthe pathogen-inactivated plasma can be transferred from the CAD to theone or more second containers to the third container under sterileconditions, wherein the third container is suitable for freezing thepathogen-inactivated plasma followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of the cryoprecipitate. In some embodiments, one or more ofthe first, second, third, and fourth supernatants is separated from oneor more of the first, second, third, and fourth precipitates in step c)within one or more fourth containers, each of which is configured to becoupled to the one or more second containers or to the third containersuch that the supernatant can be transferred from the one or more secondcontainers or the third container to the one or more fourth containersunder sterile conditions to afford a pathogen-inactivatedcryosupernatant contained within the one or more fourth containers and apathogen-inactivated cryoprecipitate contained within the one or moresecond containers or the third container.

In still another aspect, the present disclosure provides a method ofinfusing a cryosupernatant into a subject, comprising infusing into thesubject a cryosupernatant produced by the method of any of the aboveembodiments.

In still another aspect, the present disclosure provides a processingset for preparing a pathogen-inactivated cryoprecipitate, comprising a)a first container within which one or more units of a plasma can bephotochemically inactivated in the presence of a psoralen under sterileconditions; b) a compound absorption device (CAD) coupled to the firstcontainer such that the one or more units of plasma can be transferredfrom the first container to the compound absorption device under sterileconditions; and c) one or more second containers, each of which iscoupled to the compound absorption device such that the one or moreunits of plasma can be transferred from the compound absorption deviceto the one or more second containers under sterile conditions to providepathogen-inactivated plasma suitable for infusion into a subject,wherein the one or more second containers is suitable for freezing thepathogen-inactivated plasma followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of a precipitate and a supernatant. In some embodiments, eachof the one or more second containers is suitable for freezing thepathogen-inactivated plasma, followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of the cryoprecipitate and a cryosupernatant, followed byremoval of all or a portion of the cryosupernatant from the one or moresecond containers.

In still another aspect, the present disclosure provides a processingset for preparing a pathogen-inactivated cryoprecipitate, comprising a)a first container within which one or more units of a plasma can bephotochemically inactivated in the presence of a psoralen under sterileconditions; b) a compound absorption device (CAD) coupled to the firstcontainer such that the one or more units of plasma can be transferredfrom the first container to the compound absorption device under sterileconditions; c) one or more second containers, each of which is coupledto the compound absorption device such that the one or more units ofplasma can be transferred from the compound absorption device to the oneor more second containers under sterile conditions to providepathogen-inactivated plasma suitable for infusion into a subject; and d)a third container, which is configured to be coupled to the one or moresecond containers such that the pathogen-inactivated plasma can betransferred from the one or more second containers to the thirdcontainer under sterile conditions, wherein the third container issuitable for freezing the pathogen-inactivated plasma followed bythawing of the pathogen-inactivated plasma under conditions that providefor the formation of a precipitate and a supernatant. In someembodiments, the third container is suitable for freezing thepathogen-inactivated plasma, followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of the cryoprecipitate and a cryosupernatant, followed byremoval of all or a portion of the cryosupernatant from the thirdcontainer. In some embodiments, the processing set further comprises anadditional container suitable for mixing the one or more units of plasmawith a pathogen inactivation compound, wherein the additional containeris coupled to the first container such that the one or more units ofplasma in admixture with the pathogen-inactivating compound can betransferred from the additional container to the first container understerile conditions. In some embodiments, the processing set furthercomprises one or more fourth containers, each of which is configured tobe coupled to the one or more second containers or to the thirdcontainer such that the supernatant can be transferred from the one ormore second containers or the third container to the one or more fourthcontainers under sterile conditions to provide a pathogen-inactivatedcryosupernatant contained within the one or more fourth containers and apathogen-inactivated cryoprecipitate contained within the one or moresecond containers or the third container. In some embodiments, the thirdcontainer is coupled to the one or more second containers such that thesupernatant can be transferred from the one or more second containers tothe third container under sterile conditions to afford apathogen-inactivated cryosupernatant contained within the thirdcontainer and a pathogen-inactivated cryoprecipitate contained withinthe one or more second containers. In some embodiments, the thirdcontainer is configured to be coupled to the one or more secondcontainers such that the pathogen-inactivated plasma can be transferredfrom the one or more second containers to the third container understerile conditions; wherein the third container is suitable for freezingthe pathogen-inactivated plasma followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of a precipitate and a supernatant; and wherein each of theone or more fourth containers is configured to be coupled to the thirdcontainer such that the supernatant can be transferred from the thirdcontainer to the one or more fourth containers under sterile conditionsto afford a pathogen-inactivated cryosupernatant contained within theone or more fourth containers and a pathogen-inactivated cryoprecipitatecontained within the third container.

In still another aspect, the present disclosure provides a method ofpreparing a cryoprecipitate for infusion into a subject comprising: a)preparing a cryoprecipitate from pathogen-inactivated plasma; and b)freezing the cryoprecipitate; wherein the cryoprecipitate is suitablefor infusion into the subject for up to about 5 days after thawing. Insome embodiments, the cryoprecipitate is prepared from at least about550 mL and less than about 650 mL of pathogen-inactivated plasma. Insome embodiments, the cryoprecipitate is prepared from about 600 mL ofpathogen-inactivated plasma. In some embodiments, the method furthercomprises combining a first cryoprecipitate prepared from at least about550 mL and less than about 650 mL of pathogen-inactivated plasma and asecond cryoprecipitate prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma, wherein the first and thesecond cryoprecipitates are combined prior to step b). In someembodiments, the first cryoprecipitate is prepared from about 600 mL ofpathogen-inactivated plasma, and wherein the second cryoprecipitate isprepared from about 600 mL of pathogen-inactivated plasma. In someembodiments, the method further comprises combining a firstcryprecipitate prepared from 3 units of pathogen-inactivated plasma anda second cryoprecipitate prepared from 3 units of pathogen-inactivatedplasma, wherein the first and the second cryoprecipitates are combinedprior to step b).

In still another aspect, the present disclosure provides a method oftreating a disease or condition indicated for treatment by plasmaexchange in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of pathogen-inactivatedplasma composition by plasma exchange. In some embodiments, the diseaseor condition is indicated for treatment with albumin by plasma exchange.In some embodiments, the disease or condition is a disease or conditionset forth in the present disclosure. In some embodiments, the disease orcondition is Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy, myasthenia gravis, a paraproteinemic polyneuropathy,Goodpasture's syndrome, or cryoglobulinemia. In some embodiments, thedisease or condition is other than thrombocytopenic purpura (TTP) orhemolytic-uremic syndrome (HUS). In some embodiments, the disease orcondition is burn shock resuscitation. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedplasma that has not been previously frozen. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfrozen plasma. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated fresh frozen plasma. In someembodiments, the pathogen-inactivated plasma composition comprisespathogen-inactivated cryo-poor plasma. In some embodiments, the diseaseor condition is thrombocytopenic purpura (TTP) or hemolytic-uremicsyndrome (HUS). In some embodiments, the plasma exchange is achievedwith a volume of the plasma composition similar to the subject's plasmavolume. In some embodiments, the plasma exchange is achieved with avolume of the plasma composition between about 1 times and about 1.5times the subject's plasma volume. In some embodiments, the plasmaexchange is achieved with a volume of the plasma composition comprisingabout 40 mL/kg patient body weight. In some embodiments, the plasmaexchange is achieved with a volume of the plasma composition comprisingabout 60 mL/kg patient body weight. In some embodiments, the plasmaexchange is performed at least two times. In some embodiments, theplasma exchange is performed 2-5 times. In some embodiments, the plasmaexchange is performed 2-5 times within a period of two weeks. In someembodiments, the plasma exchange is performed 2-5 times within a periodof one week.

In still another aspect, the present disclosure provides a method oftreating a disease or condition indicated for treatment by infusion withintravenous immunoglobulin in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount ofpathogen-inactivated plasma composition by plasma exchange. In someembodiments, the disease or condition is a disease or condition setforth in the present disclosure. In some embodiments, the disease orcondition is Guillain-Barré syndrome, myasthenia gravis, polymyositis,dermatomyositis, or chronic inflammatory demyelinating polyneuropathy.In some embodiments, the disease or condition is other thanthrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). Insome embodiments, the pathogen-inactivated plasma composition comprisespathogen-inactivated plasma that has not been previously frozen. In someembodiments, the pathogen-inactivated plasma composition comprisespathogen-inactivated frozen plasma. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfresh frozen plasma. In some embodiments, the pathogen-inactivatedplasma composition comprises pathogen-inactivated cryo-poor plasma. Insome embodiments, the plasma exchange is achieved with a volume of theplasma composition similar to the subject's plasma volume. In someembodiments, the plasma exchange is achieved with a volume of the plasmacomposition between about 1 times and about 1.5 times the subject'splasma volume. In some embodiments, the plasma exchange is achieved witha volume of the plasma composition comprising about 40 mL/kg patientbody weight. In some embodiments, the plasma exchange is achieved with avolume of the plasma composition comprising about 60 mL/kg patient bodyweight. In some embodiments, the plasma exchange is performed at leasttwo times. In some embodiments, the plasma exchange is performed 2-5times. In some embodiments, the plasma exchange is performed 2-5 timeswithin a period of two weeks. In some embodiments, the plasma exchangeis performed 2-5 times within a period of one week. In some embodiments,the disease or condition is thrombocytopenic purpura (TTP) orhemolytic-uremic syndrome (HUS).

In still another aspect, the present disclosure provides a method oftreating a disease or condition set forth in the present disclosure. Insome embodiments, the present disclosure provides a method of treating adisease or condition selected from the group consisting ofGuillain-Barré syndrome, myasthenia gravis, polymyositis,dermatomyositis and chronic inflammatory demyelinating polyneuropathy ina subject, comprising administering to a subject in need thereof atherapeutically effective amount of pathogen-inactivated plasmacomposition by plasma exchange. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedplasma that has not been previously frozen. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfrozen plasma. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated fresh frozen plasma. In someembodiments, the pathogen-inactivated plasma composition comprisespathogen-inactivated cryo-poor plasma. In some embodiments, the plasmaexchange is achieved with a volume of the plasma composition similar tothe subject's plasma volume. In some embodiments, the plasma exchange isachieved with a volume of the plasma composition between about 1 timesand about 1.5 times the subject's plasma volume. In some embodiments,the plasma exchange is achieved with a volume of the plasma compositioncomprising about 40 mL/kg patient body weight. In some embodiments, theplasma exchange is achieved with a volume of the plasma compositioncomprising about 60 mL/kg patient body weight. In some embodiments, theplasma exchange is performed at least two times. In some embodiments,the plasma exchange is performed 2-5 times. In some embodiments, theplasma exchange is performed 2-5 times within a period of two weeks. Insome embodiments, the plasma exchange is performed 2-5 times within aperiod of one week.

In still another aspect, the present disclosure provides a method oftreating thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome(HUS) in a subject, comprising administering to a subject in needthereof a therapeutically effective amount of a pathogen-inactivatedplasma composition. In some embodiments, the composition is administeredby plasma exchange. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated cryo-poor plasma. In stillanother aspect, the present disclosure provides a method of treatingthrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of a pathogen-inactivated plasmacomposition by plasma exchange, wherein the pathogen-inactivated plasmacomposition comprises pathogen-inactivated cryo-poor plasma. In someembodiments, the pathogen-inactivated plasma composition is administeredwithin 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days afterthawing. In some embodiments, the plasma exchange is achieved with avolume of the plasma composition similar to the subject's plasma volume.In some embodiments, the plasma exchange is achieved with a volume ofthe plasma composition between about 1 times and about 1.5 times thesubject's plasma volume. In some embodiments, the plasma exchange isachieved with a volume of the plasma composition comprising about 40mL/kg patient body weight. In some embodiments, the plasma exchange isachieved with a volume of the plasma composition comprising about 60mL/kg patient body weight. In some embodiments, the plasma exchange isperformed at least two times. In some embodiments, the plasma exchangeis performed 2-5 times. In some embodiments, the plasma exchange isperformed 2-5 times within a period of two weeks. In some embodiments,the plasma exchange is performed 2-5 times within a period of one week.

In still another aspect, the present disclosure provides a method oftreating a solid organ transplant recipient to prevent animmune-mediated solid organ transplant rejection, comprisingadministering to the transplant recipient a therapeutically effectiveamount of a pathogen-inactivated plasma composition by plasma exchange,wherein the plasma exchange is prior to the transplant procedure. Insome embodiments, the immune-mediated transplant rejection is anantibody-mediated transplant rejection. In some embodiments, theantibody-mediated transplant rejection is an IgG-mediated transplantrejection. In some embodiments, the solid organ transplant is anABO-incompatible solid organ transplant. In some embodiments, the solidorgan transplant is an HLA-incompatible solid organ transplant. In someembodiments, the solid organ transplant is a renal (e.g., kidney)transplant. In some embodiments, the kidney is obtained from a livingdonor. In some embodiments, the solid organ transplant is a cardiac(e.g., heart) transplant. In some embodiments, the solid organtransplant is a liver transplant. In some embodiments, the method oftreating a solid organ transplant recipient is a method ofdesensitization to the transplant. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedplasma that has not been previously frozen. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfrozen plasma. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated fresh frozen plasma. In someembodiments, the pathogen-inactivated plasma composition comprisespathogen-inactivated cryo-poor plasma. In some embodiments, thepathogen-inactivated plasma composition is administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days after thawing. In someembodiments, the plasma exchange is achieved with a volume of the plasmacomposition similar to the subject's plasma volume. In some embodiments,the plasma exchange is achieved with a volume of the plasma compositionbetween about 1 times and about 1.5 times the subject's plasma volume.In some embodiments, the plasma exchange is achieved with a volume ofthe plasma composition comprising about 40 mL/kg patient body weight. Insome embodiments, the plasma exchange is achieved with a volume of theplasma composition comprising about 60 mL/kg patient body weight. Insome embodiments, the plasma exchange is performed at least two timesprior to the transplant procedure. In some embodiments, the plasmaexchange is performed 2-15 times prior to the transplant procedure. Insome embodiments, the method further comprises administering to thetransplant recipient a therapeutically effective amount ofpathogen-inactivated plasma composition by plasma exchange after thetransplant procedure. In some embodiments, the plasma exchange isperformed at least two times after the transplant procedure. In someembodiments, the plasma exchange is performed 2-5 times after thetransplant procedure.

In some embodiments of any of the above embodiments, thepathogen-inactivated plasma composition is administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days after thawing. In someembodiments of any of the above embodiments, the pathogen-inactivatedplasma composition is a lyophilized or freeze-dried plasma composition.In some embodiments, the pathogen-inactivated plasma composition isadministered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7days after reconstitution.

In still another aspect, the present disclosure provides a method offluid resuscitation in a subject suffering from burns, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a pathogen-inactivated plasma composition. In someembodiments, the subject is suffering from major burns comprising atleast 20% of total body surface area. In some embodiments, the method offluid resuscitation is a method of burn shock resuscitation. In someembodiments, endothelial permeability, endothelial dysfunction and/orvascular hyperpermeability is reduced by administration of thepathogen-inactivated plasma composition. In some embodiments,administration of the pathogen-inactivated plasma composition results indecreased subject mortality. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfrozen plasma. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated fresh frozen plasma. In someembodiments, the pathogen-inactivated plasma composition comprisespathogen-inactivated cryo-poor plasma. In some embodiments, thepathogen-inactivated plasma composition is administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days after thawing. In someembodiments, the pathogen-inactivated plasma composition is alyophilized or freeze-dried plasma composition. In some embodiments, thepathogen-inactivated plasma composition is administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days after reconstitution. Insome embodiments, about 1 mL to about 5 mL per kg body weight per %total burn surface area (TBSA) of the pathogen-inactivated plasmacomposition is administered to the subject. In some embodiments, avolume of the pathogen-inactivated plasma composition sufficient toachieve an increase in blood pressure to at least about 50 mmHg isadministered to the subject. In some embodiments, a volume of thepathogen-inactivated plasma composition sufficient to achieve anincrease in blood pressure to at least about 100 mmHg is administered tothe subject. In some embodiments, the pathogen-inactivated plasmacomposition is administered to the subject within about 24 hours, withinabout 20 hours, within about 16 hours, within about 12 hours, withinabout 10 hours, within about 8 hours, within about 6 hours, within about5 hours, within about 4 hours, within about 3 hours, within about 2hours or within about 1 hours after the onset of burns or medicaldiagnosis thereof. In some embodiments, pathogen-inactivated plasmacomposition is administered to the subject over a time period of about24 hours. In some embodiments, pathogen-inactivated plasma compositionis administered to the subject in multiple infusions over a time periodof about 24 hours.

In still another aspect, the present disclosure provides a method oftreating a subject suffering from burns or a trauma, the methodcomprising: administering to a subject in need thereof a therapeuticallyeffective amount of a pathogen-inactivated plasma composition. In someembodiments, the subject is suffering from burns. In some embodiments,the subject is suffering from blunt trauma. In some embodiments, thesubject is suffering from penetrating trauma. In some embodiments, thesubject is suffering from hemorrhage. In some embodiments, the subjectis suffering from internal hemorrhage. In some embodiments, the methodis a method of fluid resuscitation. In some embodiments, the methodreduces hemorrhage in the subject. In some embodiments, the methodreduces hemorrhagic shock in the subject. In some embodiments,endothelial permeability is reduced in the subject. In some embodiments,the method reduces or prevents trauma-induced endotheliopathy in thesubject. In some embodiments, the infusion or treatment results indecreased subject mortality.

In still another aspect, the present disclosure provides a method ofresuscitation from hemorrhagic shock in a subject suffering from burnsor a trauma, comprising administering to the subject a therapeuticallyeffective amount of a pathogen-inactivated plasma composition. In someembodiments, the subject is suffering from burns. In some embodiments,the subject is suffering from blunt trauma. In some embodiments, thesubject is suffering from penetrating trauma. In some embodiments, thesubject is suffering from internal hemorrhage. In some embodiments, themethod reduces hemorrhage in the subject. In some embodiments,endothelial permeability is reduced in the subject. In some embodiments,the method reduces or prevents trauma-induced endotheliopathy in thesubject. In some embodiments, the method reduces or prevents traumaticcoagulopathy in the subject. In some embodiments, the treatment resultsin decreased subject mortality.

In some embodiments of any of the above embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfrozen plasma. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated fresh frozen plasma. In someembodiments of any of the above embodiments, the pathogen-inactivatedplasma composition comprises pathogen-inactivated cryo-poor plasma. Insome embodiments of any of the above embodiments, thepathogen-inactivated plasma composition is administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days after thawing. In someembodiments of any of the above embodiments, the pathogen-inactivatedplasma composition is a lyophilized or freeze-dried plasma composition.In some embodiments, the pathogen-inactivated plasma composition isadministered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7days after reconstitution. In some embodiments of any of the aboveembodiments, the pathogen-inactivated plasma composition is firstadministered less than 24 hours after the onset of trauma. In someembodiments of any of the above embodiments, administration of thepathogen-inactivated plasma composition is followed by administration ofat least one additional intravenous fluid.

In still another aspect, the present disclosure provides a method forpreparing pathogen-inactivated cryo-poor plasma, the method comprising:

a) photochemically inactivating one or more units of plasma in thepresence of a psoralen, wherein the photochemical inactivation isperformed under sterile conditions in a first container containing theone or more units of plasma;b) transferring under sterile conditions the one or more units of plasmafrom the first container to a compound absorption device (CAD) coupledto the first container;c) transferring under sterile conditions the one or more units of plasmafrom the CAD to two or more second containers coupled to the CAD toprovide pathogen-inactivated plasma;d) transferring under sterile conditions the pathogen-inactivated plasmafrom the two or more second containers to a third container coupled tothe two or more second containers;e) freezing the pathogen-inactivated plasma followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of a cryoprecipitate and pathogen-inactivated cryo-poorplasma;f) transferring the pathogen-inactivated cryo-poor plasma to a at leasta first of the two or more second containers; andg) transferring the cryoprecipitate to a second of the two or moresecond containers. In some embodiments, at least a portion of thepathogen-inactivated cryo-poor plasma is transferred to each of at leasttwo second containers in step f), and wherein the cryoprecipitate istransferred to a third second container in step g). In some embodiments,prior to step g), the cryoprecipitate is resuspended in about 80 mL toabout 120 mL of pathogen-inactivated cryo-poor plasma. In someembodiments, prior to step g), the cryoprecipitate is resuspended inabout 100 mL of pathogen-inactivated cryo-poor plasma.

In still another aspect, the present disclosure provides a method forinfusing pathogen-inactivated cryo-poor plasma into a subject,comprising infusing into a subject in need thereof a therapeuticallyeffective amount of a pathogen-inactivated cryo-poor plasma prepared bythe method of any one of the above embodiments. In some embodiments, thesubject is suffering from one or more of burns, blunt trauma,penetrating trauma, and hemorrhage. In some embodiments, the infusionresults in fluid resuscitation of the subject. In some embodiments,infusing the pathogen-inactivated cryo-poor plasma into a subject is bytherapeutic plasma exchange. In some embodiments, the subject in needthereof is a subject suffering from thrombocytopenic purpura (TTP) orhemolytic-uremic syndrome (HUS). In some embodiments, the method furthercomprises, prior to the infusion: 1) freezing the pathogen-inactivatedcryo-poor plasma; and 2) thawing the pathogen-inactivated cryo-poorplasma. In some embodiments, the pathogen-inactivated cryo-poor plasmais infused into the subject within 1 day, 2 days, 3 days, 4 days, 5days, 6 days, or 7 days after thawing.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in treating a disease or condition indicated fortreatment by plasma exchange in a subject in need thereof. In stillanother aspect, the present disclosure provides a use of apathogen-inactivated plasma composition according to any of the aboveembodiments in the manufacture of a medicament for treating a disease orcondition indicated for treatment by plasma exchange in a subject inneed thereof

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in treating a disease or condition indicated fortreatment by infusion with intravenous immunoglobulin in a subject inneed thereof. In still another aspect, the present disclosure provides ause of a pathogen-inactivated plasma composition according to any of theabove embodiments in the manufacture of a medicament for treating adisease or condition indicated for treatment by infusion withintravenous immunoglobulin in a subject in need thereof.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in treating a disease or condition selected from thegroup consisting of Guillain-Barré syndrome, myasthenia gravis,polymyositis, dermatomyositis and chronic inflammatory demyelinatingpolyneuropathy in a subject. In still another aspect, the presentdisclosure provides a use of a pathogen-inactivated plasma compositionaccording to any of the above embodiments in the manufacture of amedicament for treating a disease or condition selected from the groupconsisting of Guillain-Barré syndrome, myasthenia gravis, polymyositis,dermatomyositis and chronic inflammatory demyelinating polyneuropathy ina subject.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition comprising pathogen-inactivatedcryo-poor plasma according to any of the above embodiments for use intreating thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome(HUS) in a subject. In still another aspect, the present disclosureprovides a use of a pathogen-inactivated plasma composition comprisingpathogen-inactivated cryo-poor plasma according to any of the aboveembodiments in the manufacture of a medicament for treatingthrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) in asubject.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in treating a solid organ transplant recipient toprevent an immune-mediated solid organ transplant rejection. In stillanother aspect, the present disclosure provides a use of apathogen-inactivated plasma composition according to any of the aboveembodiments in the manufacture of a medicament for treating a solidorgan transplant recipient to prevent an immune-mediated solid organtransplant rejection.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in treating a subject suffering from a trauma. Instill another aspect, the present disclosure provides a use of apathogen-inactivated plasma composition according to any of the aboveembodiments in the manufacture of a medicament for treating a subjectsuffering from a trauma. In some embodiments, the subject is sufferingfrom burns.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in resuscitation from hemorrhagic shock in a subjectsuffering from a trauma. In still another aspect, the present disclosureprovides a use of a pathogen-inactivated plasma composition according toany of the above embodiments in the manufacture of a medicament forresuscitation from hemorrhagic shock in a subject suffering from atrauma.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in fluid resuscitation in a subject suffering fromburns. In still another aspect, the present disclosure provides a use ofa pathogen-inactivated plasma composition according to any of the aboveembodiments in the manufacture of a medicament for fluid resuscitationin a subject suffering from burns.

In still another aspect, the present disclosure provides apathogen-inactivated plasma composition according to any of the aboveembodiments for use in burn shock resuscitation in a subject. In stillanother aspect, the present disclosure provides a use of apathogen-inactivated plasma composition according to any of the aboveembodiments in the manufacture of a medicament for burn shockresuscitation in a subject.

It is to be understood that one, some, or all of the properties of thevarious embodiments described herein may be combined to form otherembodiments. These and other aspects will become apparent to one ofskill in the art. These and other embodiments are further described bythe detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 1B shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 1C shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 2A shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 2B shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 2C shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 3A shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 3B shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 4 depicts combining two separate cryoprecipitate preparations inaccordance with some embodiments.

FIG. 5 shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

FIG. 6 shows an exemplary processing kit in accordance with someembodiments. Dotted components are optional.

DETAILED DESCRIPTION

The term “cryoprecipitate” refers to a blood product produced bycontrolled thawing of frozen plasma (e.g., whole blood-derived freshfrozen plasma, apheresis derived plasma) to form a precipitatecomprising one or more coagulation factors including without limitationfibrinogen, Factor VIII, Factor XIII, vWF, and/or fibronectin. Suchcryoprecipitate may be recovered from the liquid plasma portion, forexample, by refrigerated centrifugation. A cryoprecipitate may beresuspended in any suitable volume of plasma after recovery. Methods forpreparing a cryoprecipitate are well known in the art and providedthroughout the present disclosure.

The term “plasma” refers to any plasma blood product known in the art.In some embodiments, plasma refers to whole blood-derived fresh frozenplasma. In some embodiments, plasma refers to one or more plasma unitsfrom a whole blood donation (e.g., approximately 180-250 mL volumeeach). In some embodiments, plasma refers to one or more plasma unitsfrom an apheresis blood donation (may be up to approximately 700-800 mLeach). In some embodiments, plasma refers to a single unit. In someembodiments, plasma may be pooled from multiple units. In someembodiments, plasma may contain one or more additional components,including, without limitation, one or more pathogen-inactivationcompounds and/or byproducts of a pathogen-inactivation process.

The terms “cryo-poor plasma”, “cryosupernatant” and “cryo-reducedplasma” refer to the supernatant recovered after subjecting thawedfrozen plasma (e.g., fresh frozen plasma, FFP) to a cryoprecipitationprocess, and separating the liquid supernatant from the precipitatedplasma components or factors (cryoprecipitate). The cryo-poor plasma(CPP) supernatant generally contains reduced levels of various plasmacomponents or factors (e.g., factor VIII, factor XIII, vWF, fibrinogen)that were precipitated and removed during the preparation ofcryoprecipitate.

The term “suitable for infusion” refers to any blood product (e.g., acryoprecipitate) able to be used for an infusion (e.g., a transfusion)into a subject (e.g., a human patient) according to medical judgement.In some embodiments, suitability refers to having sufficient biologicalactivity for its intended use, i.e., for use where a transfusion ofhuman coagulation factors is indicated, including, without limitation,control of bleeding associated with fibrinogen deficiency, treatingFactor XIII deficiency, treating Factor VIII deficiency, treating vonWillebrand disease, maintenance of hemostasis, treating disseminatedintravascular coagulation (DIC) or high volume hemorrhage, and/or makingfibrin sealant. In some embodiments, suitability refers to havingsufficient safety, e.g., that the product has undergone a treatment thatimproves product safety (e.g., pathogen inactivation) and/ordemonstrates satisfactory performance with respect to one or moresafety-related measurements (such as viral or bacterial titer).Photochemical inactivation of pathogens in blood product units usingamotosalen and UVA light as described herein is well established toprovide such a blood product (e.g., cryoprecipitate) that is suitablefor transfusion into humans. In some embodiments, suitability refers tomeeting one or more standards (e.g., having a level of a biologicalactivity or a biological component, a safety criterion, and the like)established by an accrediting agency or regulatory body that governsinfusion practices, such as the AABB.

“Pathogen-inactivated” as used herein describes a blood product (e.g., acryoprecipitate or plasma) that has undergone processing (e.g., by themethods described herein) to inactivate pathogens that may be present.It is understood that a pathogen-inactivated cryoprecipitate may includea cryoprecipitate that has itself undergone pathogen inactivation, or acryoprecipitate made from a pathogen-inactivated blood product (e.g.,plasma, whole blood, and the like). It is further understood that theprocess does not necessarily inactivate completely all pathogens thatmay be present, but substantially reduces the amount of one or morepathogens to significantly reduce the risk of a transfusion-associateddisease. The inactivation of a pathogen may be assayed by measuring thenumber of infective pathogens (e.g., virus or bacteria) in a certainvolume, and the level of inactivation is typically represented by thelog reduction in the infectivity of the pathogen, or log reduction intiter. Methods of assaying log reduction in titer, and measurementsthereof for pathogen inactivation are known in the art. Methods ofassaying log reduction in titer, and measurements thereof for pathogeninactivation are described, for example, in U.S. Pat. No. 7,655,392, thedisclosure of which is hereby incorporated by reference as it relates toassays for pathogen inactivation. As such, for any given pathogen, knownamounts can be added to a test unit of cryoprecipitate or plasma toassess how much inactivation results from the process, where typicallythe pathogen inactivation process results in at least about 1 logreduction in titer, or about 2 log, about 3 log, about 4 log, or atleast about 5 log reduction in titer. While the methods as describedherein are applicable to any pathogen-inactivation treatment, it isdesirable that the pathogen-inactivation treatment is capable ofinactivating a variety of pathogens to at least 1 log reduction intiter, including a pathogen selected from the group consisting of HIV-1,HBV, HCV, HTLV-1, HTLV-2, West Nile virus, Escherichia coli, Klebsiellapneumoniae, Yersinia enterocolitica, Staphylococcus epidermidis,Staphylococcus aureus, Treponema pallidum, Borrelia burgdorferi,Plasmodium falciparum, Trypanosoma cruzi, and Babesia microti.

The term “pathogen inactivation compound” means any suitable compound,such as a small organic compound, that can be used to inactivate apathogen that may be present in a blood product such as cryoprecipitateor plasma. A “photoactivated pathogen inactivation compound” is asuitable compound that requires some level of light (e.g., ultravioletlight) in order to sufficiently inactivate a pathogen. Such compoundsare preferred in the inactivation of pathogens in blood products such ascryoprecipitate or plasma as they provide control over the inactivationprocess. Such photoactivated pathogen inactivation compounds describedherein include psoralens, isoalloxazines, alloxazines, phthalocyanines,phenothiazines, and porphyrins, where these terms are understood toencompass a general class of compounds, i.e. the core compound andsuitable derivatives thereof. For example, psoralens or a psoralengenerally describes the psoralen core compound and any derivativethereof (e.g. amotosalen), isoalloxazines or an isoalloxazine generallydescribes the isoalloxazine core and any derivative thereof (e.g.riboflavin), and so forth. Such derivatives comprise the core compoundstructure as well as additional substituents on the core. Descriptionsof such compounds include any salts thereof.

The term “amotosalen” means the compound3-(2-aminoethoxymethyl)-2,5,9-trimethylfuro[3,2-g]chromen-7-one and anysalts thereof. The compound may also be referred to as3-[(2-aminoethoxy)methyl]-2,5,9-trimethyl-7H-furo[3,2-G][1]benzopyran-7-one-hydrochloride.The compound may also be referred to as4′-(4-amino-2-oxa)butyl-4,5′,8-trimethyl psoralen. Where theinactivation of blood products such as cryoprecipitate or plasmaincludes adding amotosalen HCl (the HCl salt of amotosalen) to a unit ofblood product, the removal of this compound from the unit is not limitedto the removal of amotosalen HCl, as the amotosalen can be present insolution as other salts or as the free base. As used in the methodsdescribed herein, removal of amotosalen means removal of the compound inany form, e.g. as the free base or as any salt, as measured by theassays described herein. Treatment or processing of blood products byamotosalen inactivation refers to combining a blood product (e.g., unitof cryoprecipitate or plasma, individual unit, pooled) with amotosalenand illuminating with a suitable dose of UVA light in order toinactivate pathogens that may be present. In some embodiments,amotosalen-inactivated cryoprecipitate has been pathogen inactivated, orthe plasma from which the cryoprecipitate has been produced has beenpathogen inactivated, according to commercial methods, or by similarmethods.

The term “under sterile conditions” as used herein refers to maintainingthe sterility of the system, for example by connection of two bags froma blood processing set, or refers to a means by which the process doesnot introduce contamination. For example, as used in the methodsdescribed herein, a source unit of blood product such as cryoprecipitateor plasma comprising a tubing for connection to a processing set orcontainer of pathogen inactivation compound comprising a similar tubingmay be joined under sterile condition by methods known in the art, forexample using a sterile connecting device, which acts to melt or weldthe tubing together to provide a sterile flow path between the twocontainers. Similarly, when methods described herein describe sealingoff such tubing, the sealing is done under sterile conditions, forexample using a tubing welder.

A “blood-collection bag” can be any bag used for collecting blood from adonor as known in the art. Blood collected in a blood-collection bagthat is not attached to other bags may be centrifuged to separate theblood into blood components. Then, the blood-collection bag is steriledocked to a number of satellite bags that corresponds to the number ofblood products it has been determined to manufacture from the wholeblood. Blood in a blood-collection bag may be processed, such as bycentrifuging and/or freezing, in the blood-collection bag beforeseparation into satellite bags, or the blood may be transferred (bygravity or by pumping) from the blood-collection bag to ablood-processing bag.

A “blood-processing bag” is any such bag known in the art, other thanthe blood-collection bag, used for processing blood. Theblood-processing bag may be pre-connected to the blood-collection bag orattached to the blood-collection bag through sterile docking. Bloodtransferred to a blood-processing bag may be centrifuged. Prior tocentrifuging or immediately after centrifuging, the blood-processing bagis sterile docked to a number of satellite bags that corresponds to thenumber of blood products it has been determined to manufacture from thewhole blood.

Blood Collection and Cryoprecipitate/Cryo-Poor Plasma Preparation

Whole blood for use in the preparation of cryoprecipitate and cryo-poorplasma as described herein may be collected by a variety of proceduresknown in the art. One of the most common blood collection techniques, isthe “manual” collection of whole blood from healthy donors. As commonlyunderstood and as used herein, manual collection refers to a collectionmethod where whole blood is allowed to drain from the donor and into acollection container without the use of external pumps or similardevices. This is in contrast to so-called automated procedures whereblood is withdrawn from a donor and further processed by an instrumentthat typically includes a processing or separation device and pumps formoving blood or blood components into and out of the device. Automatedcell separation systems may be used to collect plasma from a donor by anapheresis procedure (e.g., plasmapheresis), while returning other bloodcomponents to the donor. Apheresis collected plasma also may be used forthe preparation of cryoprecipitate and cryo poor plasma using themethods and kits provided herein.

In some embodiments, plasma of the present disclosure includes plasmafrozen within 8 hours of donation or subjected to a pathogeninactivation process within 8 hours of donation and then frozen (e.g.,fresh frozen plasma, FFP), or plasma frozen within 24 hours of donationor subjected to a pathogen inactivation process within 24 hours ofdonation and then frozen (e.g., PF24). In some embodiments, plasma ofthe present disclosure includes liquid plasma (e.g., never frozenplasma) subjected to a pathogen inactivation process and not frozen forstorage and then thawed prior to the initiation of the cryoprecipitationfreeze/thaw process. In some embodiments, plasma refers to one or moreplasma units from a whole blood donation (e.g., approximately 180-250 mLvolume each). In some embodiments, plasma refers to one or more plasmaunits from an apheresis blood donation (e.g., apheresis collectedplasma) (may be up to approximately 700-800 mL each).

Regardless of whether the blood collection technique is manual orautomated, withdrawing blood from the donor typically includes insertinga vein access device, such as a needle, into the donor's arm (and, morespecifically, the donor's vein) and withdrawing blood from the donorthrough the needle. The “venipuncture” needle typically has attached toit, one end of a plastic tube that provides a flow path for the blood.The other end of the plastic tube terminates in one or more pre-attachedplastic blood containers or bags for collecting the blood. The needle,tubing and containers make up a blood collection set which ispre-sterilized and disposed of after a single use. The sterile bloodcollection container typically serves as the primary container forinitial separation of blood components (e.g., separation of plasma fromred blood cells and platelets).

The blood collection container and plastic tubing may also include avolume of a liquid anticoagulant, while in the automated technique, aseparate container of anticoagulant may be provided from which theanticoagulant is metered into the flow path and mixed with the incomingwhole blood. Anticoagulant is required because of the tendency of bloodto clot and adhere to the walls of the plastic surfaces which it.Exemplary anticoagulants are well known in the art and may include, butare not limited to, an anticoagulant citrate phosphate dextrose (CPD)solution, an anticoagulant citrate phosphate double dextrose (CP2D)solution, an anticoagulant citrate phosphate dextrose adenine (CPDA)solution (e.g., CPDA-1), an acid citrate dextrose (ACD) solution (e.g.,ACD-A), and an anticoagulant sodium citrate 4% w/v solution.

Blood may be identified or characterized with respect to one or moreparameters, such as for example, hematocrit. Such identification orcharacterization is typically prior to or shortly after bloodcollection, but prior to subjecting the collected whole blood to furtherprocessing, such as according to the methods provided herein. Inaddition, at or near the time of collection and prior to transfusion toa patient, tests may be performed for determining blood type and thepresence of pathogens such as virus, bacteria and/or other foreignsubstances in the donor's blood. Such testing generally requiresobtaining a sample of the donor's blood. Generally sampling of blood maybe before, during or after donation, but without compromising thesterility of the system and/or the collected blood product. For example,samples may be commonly obtained by finger stick, heel stick orvenipuncture. In the case where blood for hemoglobin testing is gatheredwith a capillary stick, a single-use sterile lancet may be used. Anotherwell-known technique is to simply withdraw or collect the bloodremaining in the flow path of the collection set after donation. Thisinvolves removing the needle from the donor, inserting the needle into avacuum sealed sampling vial or tube and allowing the blood from the flowpath to drain into the vial. Another alternative is to clamp off theflow path near the collection container and divert the blood beingwithdrawn from the donor to a collection (sampling) vial or tube. Thisprocedure may employ a particular type of disposable tubing set having apre-attached sampling site on the main flow path. Blood at or near thesampling site may be obtained by piercing the sampling site with aseparately provided needle or other piercing device, and attaching asampling vial thereto. To minimize the risk that the incoming blood willbe exposed to the outside environment, the sample is typically collectedafter completion of the blood donation. Alternatively, some collectionbags or collection sets include diversion pouches to sequester a portion(e.g., the first 20 ml) of blood collected. Another example of a bloodsampling system is described in U.S. Pat. No. 5,167,656, which describesblood collection sets with an enlarged sample collection portionincluded in the flow path. Blood for sampling is collected in theenlarged portion by clamping off the flow path near the collectioncontainer and allowing the enlarged tubing portion to fill with blood.

Plasma useful for cryoprecipitate preparation and cryo-poor supernatantas described herein may be recovered from whole blood by a variety ofprocedures known in the art. For example, plasma may be recovered bycentrifuging whole blood at low speed (e.g., approximately 1000-3000 rpmfor approximately 10-20 minutes, optionally under refrigeration),followed by recovery of the plasma fraction. In some embodiments, theplasma may be depleted of platelets (e.g., by centrifugation at higherspeeds and/or longer times within the above ranges, such asapproximately 2000-3000 rpm for approximately 15-20 minutes, orapproximately 5000×g). Plasma may also be separated from whole blood byhigher speed centrifugation, such as for example 5000×g for 10 min at 4°C. Plasma collected by apheresis methods (e.g., plasmapheresis) are alsowell known in the art.

Methods for producing cryoprecipitate and cryo-poor plasma from plasmaare well known in the art and described and exemplified herein.Typically individual units of whole blood derived plasma used forpreparation of cryoprecipitate are frozen within 8 hours of donation andthe frozen plasma (e.g., whole blood-derived fresh frozen plasma, FFP)may be thawed in a temperature controlled apparatus, such as a waterbath. The present disclosure also contemplates that whole blood derivedplasma frozen within 24 hours of donation (e.g., PF24) and plasmaproduced by apheresis (e.g., frozen with 8 hours, frozen within 24hours) may be used. In certain embodiments, previously collected plasmafrozen for storage (e.g., FFP, PF24), may be thawed and, if desiredcombined (e.g., pooled), prior to initiating a cryoprecipitationfreeze/thaw process. For thawing, the temperature may be sufficientlylow (e.g., at approximately 4° C., or between about 1° C. and about 6°C.) so as to result in a controlled, gradual thawing. For example, thethawing may take place over a total time of between about 4 hours andabout 7-8 hours, 8-10 hours, or overnight. As discussed in greaterdetail supra, individual units (e.g., 200 mL units, as defined by anaccepted standard such as AABB) of plasma may be used to produce acryoprecipitate and/or cryo-poor plasma, or more than one individualunit (e.g., 200 mL units) of plasma may be pooled to produce acryoprecipitate and/or cryo-poor plasma (e.g., 550-650 mL of plasma).For pooled plasma, a larger suitable bag such as a 1000 mL PVC bag(e.g., a Fenwal transfer pack) or any blood product compatible bag ofsufficient volume (e.g., 800 mL, 600 mL) may be used to produce thecryoprecipitate and/or cryo-poor plasma. In some embodiments, the totalthaw time may be dependent on the volume of plasma; e.g., a 200-250 mLunit of plasma may thaw for approximately 4.5 hours, whereas 550-650 mLof plasma may take approximately 6.5 hours. After thawing, the plasmamay be centrifuged, e.g., under refrigeration (such as at approximately4° C.) for approximately 10-15 minutes at approximately 4200 rcf(optionally with a slow stop) to separate the cryoprecipitate from thecryo-poor plasma (cryosupernatant). The cryoprecipitate may be separatedfrom the cryo-poor plasma, e.g., by inversion to remove the cryo-poorplasma, or through use of a plasma expressor to remove the cryo-poorplasma, with the cryo-poor plasma collected by transfer into one or moreseparate containers

In some embodiments, cryoprecipitate and/or cryo-poor plasma may befrozen after production. As the cryoprecipitate may be derived fromplasma that has itself been frozen, “re-freezing” the cryoprecipitate asused herein refers to freezing a cryoprecipitate after producing thecryoprecipitate (e.g., after the initial plasma freezing step, after theprecipitation step). Advantageously, this allows the cryoprecipitate tobe stored for later use. In some embodiments, cryoprecipitate may bestored at about −18° C. or lower (e.g., according to AABB standards).

After freezing (and optional frozen storage), cryoprecipitate and/orcryo-poor plasma may be thawed. Methods for thawing frozencryoprecipitate and/or cryo-poor plasma are well known in the art. As anon-limiting example, cryoprecipitate and/or cryo-poor plasma may bethawed in a plasma thawer (e.g., those commercially available fromHelmer Scientific). In some embodiments, cryoprecipitate and/orcryo-poor plasma may be thawed at about 35° C. In some embodiments,cryoprecipitate and/or cryo-poor plasma may be thawed for approximately5-10 minutes. In some embodiments, after thawing, the cryoprecipitatemay be mixed, e.g., by agitation. In some embodiments, cryoprecipitatemay be allowed to thaw for two or more intervals, which may optionallybe separated by one or more mixing steps. In some embodiments,cryoprecipitate may be thawed for approximately 5-10 minutes, mixed, andallowed to continue thawing for approximately 5-10 minutes.

In some embodiments, cryoprecipitate and/or cryo-poor plasma may belyophilized or freeze-dried. Freeze-dried and lyophilized blood productcompositions are known in the art. For example, freeze-dried plasma(FDP) and lyophilized plasma have been used in patients suffering fromtraumatic injury (see, e.g., Inaba, K. (2011) J. Trauma 70:S57-8 andSailliol, A. et al. (2013) Transfusion 53 Suppl 1:65S-71S).

For each of the parameters set forth in the methods provided herein,techniques for determination or measurement of the parameters are wellknown in the art.

Cryoprecipitate and Cryo-Poor Plasma Compositions

Described infra are various exemplary parameters and properties that maycharacterize a cryoprecipitate (or a composition comprising acryoprecipitate) and/or cryo-poor plasma of the present disclosure. Itwill be appreciated by one of skill in the art that these exemplarycharacteristics and embodiments may be combined in any number orcombination, unless otherwise indicated by context. These exemplarycharacteristics and embodiments may be combined with any of the otherembodiments or aspects described elsewhere herein in any number orcombination, unless otherwise indicated by context.

Certain aspects of the present disclosure relate to compositionscomprising a cryoprecipitate suitable for infusion into a subject. Asdisclosed herein, these compositions are suitable for infusion into asubject for a longer duration after thawing (e.g., thawing after frozencryoprecipitate storage) than is currently prescribed by existingguidelines (e.g., the compositions have an extended period before expiryafter thawing). Such compositions may find use, inter alia, intreatments (e.g., infusions) related to control of bleeding associatedwith fibrinogen deficiency, treating Factor XIII deficiency, treatingvon Willebrand disease, maintenance of hemostasis, treating disseminatedintravascular coagulation (DIC) or high volume hemorrhage, and/or makingfibrin sealant.

Certain aspects of the present disclosure relate to compositionscomprising a cryo-poor plasma suitable for infusion into a subject. Suchcompositions may find use, inter alia, in improved treatment methodsusing such compositions for therapeutic plasma exchange or infusion forindications, such as, but not limited to trauma and/or burns.

In some embodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) or cryo-poor plasma is suitable for infusion into asubject at least 6 hours, at least 12 hours, at least 24 hours, at least36 hours, at least 48 hours, at least 60 hours, at least 72 hours, atleast 84 hours, at least 96 hours, at least 108 hours, at least 120hours, at least 132 hours, at least 144 hours, at least 156 hours, or atleast 168 hours after thawing. In some embodiments, a cryoprecipitate orcryo-poor plasma is suitable for infusion into a subject within 6 hours,within 12 hours, within 24 hours, within 36 hours, within 48 hours,within 60 hours, within 72 hours, within 84 hours, within 96 hours,within 108 hours, within 120 hours, within 132 hours, within 144 hours,within 156 hours, or within 168 hours after thawing. In someembodiments, the cryoprecipitate or cryo-poor plasma is suitable forinfusion into a subject for a number of hours after thawing that is lessthan about any of the following numbers of hours: 168, 156, 144, 132,120, 108, 96, 84, 72, 60, 48, 36, 24, or 12. In some embodiments, thecryoprecipitate is or cryo-poor plasma suitable for infusion into asubject for a number of hours after thawing (e.g., after thawing andresuspension of the cryoprecipitate) that is greater than about any ofthe following numbers of hours: 0, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24,36, 48, 60, 72, 84, 96, 108, 120, 132, 144, or 156. That is, the numberof hours after thawing for which the cryoprecipitate or cryo-poor plasmais suitable for infusion into a subject may be any number of hourswithin a range having an upper limit of 168, 156, 144, 132, 120, 108,96, 84, 72, 60, 48, 36, 24, or 12 hours and an independently selectedlower limit of 0, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, 72,84, 96, 108, 120, 132, 144, or 156 hours, wherein the upper limit isgreater than the lower limit. In some embodiments, the cryoprecipitateis suitable for infusion into a subject immediately after thawing andresuspension of the cryoprecipitate (e.g., 0 hours after thawing). Insome embodiments, the cryoprecipitate or cryo-poor plasma may besuitable for infusion into a subject for about 0 to about 168 hours,about 0 to about 144 hours, about 0 to about 120 hours after thawing,about 0 to about 96 hours after thawing, about 0 to about 72 hours afterthawing, or about 0 to about 48 hours after thawing. In someembodiments, the cryoprecipitate may be suitable for infusion into asubject for about 6 to about 168 hours, about 6 to about 144 hours, orabout 6 to about 120 hours after thawing. In some embodiments, thecryoprecipitate may be suitable for infusion into a subject for about 12to about 168 hours, about 12 to about 144 hours, or about 12 to about120 hours after thawing. In some embodiments, the cryoprecipitate may besuitable for infusion into a subject for about 24 to about 168 hours,about 24 to about 144 hours, or about 24 to about 120 hours afterthawing. In some embodiments, the cryoprecipitate may be suitable forinfusion into a subject for about 36 to about 168 hours, about 36 toabout 144 hours, or about 36 to about 120 hours after thawing. In someembodiments, the cryoprecipitate may be suitable for infusion into asubject for about 48 to about 168 hours, about 48 to about 144 hours, orabout 48 to about 120 hours after thawing.

In some embodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) or cryo-poor plasma is suitable for infusion into asubject at least 1 day, at least 2 days, at least 3 days, at least 4days, at least 5 days, at least 6 days, or at least 7 days afterthawing. In some embodiments, the cryoprecipitate or cryo-poor plasma issuitable for infusion into a subject within 1 day, within 2 days, within3 days, within 4 days, within 5 days, within 6 days, or within 7 daysafter thawing. In some embodiments, a cryoprecipitate or cryo-poorplasma is suitable for infusion into a subject for a number of daysafter thawing that is less than about any of the following numbers ofdays: 7, 6, 5, 4, 3, or 2. In some embodiments, the cryoprecipitate orcryo-poor plasma is suitable for infusion into a subject for a number ofdays after thawing (e.g., after thawing and resuspension of thecryoprecipitate) that is greater than about any of the following numbersof days: 0, 1, 2, 3, 4, 5, or 6. In some embodiments, thecryoprecipitate or cryo-poor plasma is suitable for infusion into asubject immediately after thawing and resuspension of thecryoprecipitate (e.g., 0 days after thawing). That is, the number ofdays after thawing for which the cryoprecipitate or cryo-poor plasma issuitable for infusion into a subject may be any number of days within arange having an upper limit of 7, 6, 5, 4, 3, or 2 days and anindependently selected lower limit of 0, 1, 2, 3, 4, 5, or 6 days,wherein the upper limit is greater than the lower limit. In someembodiments, the cryoprecipitate or cryo-poor plasma may be suitable forinfusion into a subject for about 0 to about 7 days, about 0 to about 6days, about 0 to about 5 days, about 0 to about 4 days, about 0 to about3 days, or about 0 to about 2 days after thawing. In some embodiments,the cryoprecipitate or cryo-poor plasma may be suitable for infusioninto a subject for about 1 to about 7 days, about 1 to about 6 days, orabout 1 to about 5 days after thawing. In some embodiments, thecryoprecipitate or cryo-poor plasma may be suitable for infusion into asubject for about 2 to about 7 days, about 2 to about 6 days, or about 2to about 5 days after thawing.

In some embodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) or cryo-poor plasma is stored at room temperature afterthawing, e.g., for the interval between thawing and use (e.g., in aninfusion). In some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) or cryo-poor plasma is stored at betweenabout 2° C. and about 25° C. after thawing, e.g., for the intervalbetween thawing and use (e.g., in an infusion). In some embodiments, acryoprecipitate (or a composition comprising a cryoprecipitate) orcryo-poor plasma is stored at between about 20° C. and about 24° C.after thawing, e.g., for the interval between thawing and use (e.g., inan infusion). In some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) or cryo-poor plasma is stored at about 22°C. after thawing, e.g., for the interval between thawing and use. Insome embodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) or cryo-poor plasma is stored at 2° C. and about 6° C.after thawing, e.g., for the interval between thawing and use (e.g., inan infusion). In some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) or cryo-poor plasma is stored afterthawing, e.g., for the interval between thawing and use (e.g., in aninfusion) according to standards set by AABB, the American Red Cross oranother accrediting, regulatory, or standard-setting agency.

It is well known in the art that different types of blood donationscontaining plasma may have different associated volumes. The volume ofplasma obtained from a whole blood donation may vary, depending upon,for example, the volume of whole blood collected, the size of thecollection bag (e.g., 450 mL, 500 mL), the donor percent hematocrit andprocessing conditions (e.g., centrifugation conditions). For example, incertain embodiments, a whole blood donation typically yields anapproximately 180-250 mL (e.g., approximately 200 mL) unit of plasma(e.g., whole blood derived plasma), whereas the volume of plasma from asingle apheresis donation or sample (e.g., apheresis collected plasma)may yield from about 200 mL up to approximately 700-800 mL, depending ona variety of factors including donor size (e.g., body weight). In someembodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) and/or cryo-poor plasma of the present disclosure maybe obtained or prepared from about 180 mL or 200 mL to about 250 mL or300 mL or 325 mL of plasma. For example, the cryoprecipitate and/orcryo-poor plasma may be obtained from one approximately 200 mL unit(e.g., AABB defined unit, AABB unit volume) volume of plasma, such asfrom a single whole blood donation. In other embodiments, acryoprecipitate (or a composition comprising a cryoprecipitate) and/orcryo-poor plasma of the present disclosure may be obtained from at leastabout 300 mL, at least about 400 mL, at least about 500 mL, or at leastabout 600 mL or more of plasma. In other embodiments, a cryoprecipitate(or a composition comprising a cryoprecipitate) and/or cryo-poor plasmaof the present disclosure may be obtained from at least about 300 mL, atleast about 400 mL, at least about 500 mL, or at least about 600 mL ormore of plasma. In other embodiments, a cryoprecipitate (or acomposition comprising a cryoprecipitate) of the present disclosure maybe obtained from at least about 550 mL and less than 650 mL of plasma.In some embodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) and/or cryo-poor plasma of the present disclosure maybe obtained from at least about 570 mL and less than about 620 mL ofplasma. In some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) and/or cryo-poor plasma of the presentdisclosure may be obtained from at least about 600 mL and less thanabout 650 mL of plasma. In certain embodiments, a cryoprecipitate (or acomposition comprising a cryoprecipitate) and/or cryo-poor plasma of thepresent disclosure may be obtained from about 600 mL of plasma. Forexample, a cryoprecipitate and/or cryo-poor plasma may be obtained frompooling multiple AABB unit volumes of plasma (e.g., to yield 550-650mL), a single apheresis sample (e.g., having 550-650 mL or more), orfrom pooling multiple cryoprecipitates or cryo-poor plasmas obtainedfrom different samples of plasma.

As such, in some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) and/or cryo-poor plasma of the presentdisclosure may contain cryoprecipitate and cryo-poor plasma,respectively, obtained or prepared from one donor. In other embodiments,a cryoprecipitate (or a composition comprising a cryoprecipitate) of thepresent disclosure and/or cryo-poor plasma may contain cryoprecipitateand/or cryo-poor plasma, respectively, obtained or prepared from morethan one donor (e.g., prepared from more than one plasma donation,prepared from more than one plasma unit). In some embodiments, acryoprecipitate (or a composition comprising a cryoprecipitate) and/orcryo-poor plasma of the present disclosure may contain cryoprecipitateand/or cryo-poor plasma, respectively, obtained or prepared from 2-12donors. In some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) and/or cryo-poor plasma of the presentdisclosure may contain cryoprecipitate and/or cryo-poor plasma,respectively, prepared from plasma obtained from 2-6 donors. Forexample, in some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) and/or cryo-poor plasma of the presentdisclosure may contain cryoprecipitate and/or cryo-poor plasma,respectively, prepared from plasma obtained from 1, 2, 3, 4, 5, or 6donors. In some embodiments, a cryoprecipitate (or a compositioncomprising a cryoprecipitate) and/or cryo-poor plasma of the presentdisclosure may contain cryoprecipitate and/or cryo-poor plasma,respectively, obtained or prepared from 7-12 donors. For example, insome embodiments, a cryoprecipitate (or a composition comprising acryoprecipitate) and/or cryo-poor plasma of the present disclosure maycontain cryoprecipitate and/or cryo-poor plasma, respectively, preparedfrom plasma obtained from 7, 8, 9, 10, 11 or 12 donors.

In some embodiments, a cryoprecipitate composition and/or cryo-poorplasma of the present disclosure may contain more than onecryoprecipitate (e.g., individual cryoprecipitate preparations) and/orcryo-poor plasma, respectively. For example, in some embodiments, acryoprecipitate composition and/or cryo-poor plasma of the presentdisclosure may contain a first cryoprecipitate and/or cryo-poor plasma,respectively, obtained from pathogen-inactivated plasma and a secondcryoprecipitate and/or cryo-poor plasma, respectively, obtained frompathogen-inactivated plasma. In some embodiments, a cryoprecipitatecomposition and/or cryo-poor plasma of the present disclosure maycontain a first cryoprecipitate and/or cryo-poor plasma, respectively,obtained from 2 units of pathogen-inactivated plasma and a secondcryoprecipitate and/or cryo-poor plasma, respectively, obtained from 2units of pathogen-inactivated plasma. In some embodiments, acryoprecipitate composition and/or cryo-poor plasma of the presentdisclosure may contain a first cryoprecipitate and/or cryo-poor plasma,respectively, obtained from 3 units of pathogen-inactivated plasma and asecond cryoprecipitate and/or cryo-poor plasma, respectively, obtainedfrom 3 units of pathogen-inactivated plasma. In some embodiments, thefirst and the second cryoprecipitates and/or cryo-poor plasma arecombined prior to re-freezing for storage. In some embodiments, thefirst and the second cryoprecipitates and/or cryo-poor plasma arecombined prior to use (e.g., in an infusion), and/or prior to storage atroom temperature or under refrigeration. In some embodiments, acryoprecipitate composition and/or cryo-poor plasma of the presentdisclosure may contain pathogen-inactivated plasma pooled from at least3, at least 4, at least 5, or at least 6 units of pathogen-inactivatedplasma. In some embodiments, a cryoprecipitate composition and/orcryo-poor plasma of the present disclosure may containpathogen-inactivated plasma pooled from at least 7, at least 8, at least9, at least 10, at least 11, or at least 12 units ofpathogen-inactivated plasma. In some embodiments, a cryoprecipitatecomposition and/or cryo-poor plasma of the present disclosure maycontain pathogen-inactivated plasma pooled from at least 7, at least 8,at least 9, at least 10, at least 11, or at least 12 units ofpathogen-inactivated plasma. In certain embodiments, a cryoprecipitatecomposition and/or cryo-poor plasma of the present disclosure maycontain pathogen-inactivated plasma pooled from at least 3 units ofpathogen-inactivated plasma. In certain embodiments, a cryoprecipitatecomposition and/or cryo-poor plasma of the present disclosure maycontain pathogen-inactivated plasma pooled from at least 6 units ofpathogen-inactivated plasma.

In some embodiments, a cryoprecipitate composition of the presentdisclosure may be generated from plasma that has not been subject topathogen inactivation, then the cryoprecipitate itself may be subjectedto pathogen-inactivation (and, optionally, frozen for storage afterpathogen inactivation). In some embodiments, the pathogen inactivatedcryoprecipitate may be stored at 2-25° C. (e.g., 2-6° C., 20-24° C.)until use for infusion. In some embodiments, a cryoprecipitate may beprepared from plasma and subsequently subjected to pathogeninactivation. In some embodiments, the plasma has not been subject topathogen inactivation. In some embodiments, multiple cryoprecipitatepreparations made from plasma (e.g., plasma that has not been subject topathogen inactivation) may be pooled together, then subject to pathogeninactivation. Advantageously, this enables the pathogen inactivation ofa large volume of cryoprecipitate (e.g., a pooled cryoprecipitatecomposition) in one step and/or one container. In other embodiments,multiple cryoprecipitate preparations prepared from plasma (e.g., plasmathat has not been subject to pathogen inactivation) may be subject topathogen inactivation, then pooled together. In some embodiments, thepathogen-inactivated cryoprecipitate (e.g., pooled cryoprecipitate) isfrozen for storage. Any desired volume of cryoprecipitate may be subjectto pathogen inactivation and optionally pooled (e.g., before or afterpathogen inactivation). For example, in some embodiments, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least 10, at least 11, or atleast 12 preparations or units of cryoprecipitate may be pooledtogether, e.g., before or after pathogen inactivation. In someembodiments, the cryoprecipitate is prepared from at least about 550 mLand less than about 650 mL of plasma. In some embodiments, thecryoprecipitate is prepared by pooling two or more cryoprecipitate units(e.g., before or after pathogen inactivation), each cryoprecipitate unithaving been prepared from at least about 550 mL and less than about 650mL of plasma. In some embodiments, the cryoprecipitate is prepared bypooling two or more, three or more, four or more, five or more, six ormore, seven or more, eight or more, nine or more, ten or more, eleven ormore, or twelve or more cryoprecipitate units (e.g., before or afterpathogen inactivation), each cryoprecipitate unit having been preparedfrom at least about 150 mL and less than about 250 mL of plasma, e.g.,about 200 mL of plasma. In some embodiments, the cryoprecipitate isprepared by pooling two or more, three or more, four or more, five ormore, six or more, seven or more, eight or more, nine or more, ten ormore, eleven or more, or twelve or more cryoprecipitate units (e.g.,before or after pathogen inactivation), each cryoprecipitate unit havingbeen prepared from a whole blood derived plasma unit.

In some embodiments, a cryoprecipitate composition of the presentdisclosure may contain a first cryoprecipitate obtained or prepared fromat least about 550 mL and less than 650 mL of pathogen-inactivatedplasma, and a second cryoprecipitate obtained or prepared from at leastabout 550 mL and less than 650 mL of pathogen-inactivated plasma. Insome embodiments, a cryoprecipitate composition of the presentdisclosure may contain a first cryoprecipitate obtained or prepared fromat least about 570 mL and less than 620 mL of pathogen-inactivatedplasma, and a second cryoprecipitate obtained or prepared from at leastabout 570 mL and less than 620 mL of pathogen-inactivated plasma. Insome embodiments, a cryoprecipitate composition of the presentdisclosure may contain a first cryoprecipitate obtained or prepared fromat least about 600 mL and less than 650 mL of pathogen-inactivatedplasma, and a second cryoprecipitate obtained or prepared from at leastabout 600 mL and less than 650 mL of pathogen-inactivated plasma. Incertain embodiments, a cryoprecipitate composition of the presentdisclosure may contain a first cryoprecipitate obtained or prepared fromabout 600 mL of pathogen-inactivated plasma, and a secondcryoprecipitate obtained or prepared from about 600 mL ofpathogen-inactivated plasma. In some embodiments, a cryoprecipitatecomposition of the present disclosure may contain a firstcryoprecipitate obtained or prepared from at least about 150 mL and lessthan about 250 mL of pathogen-inactivated plasma, and a secondcryoprecipitate obtained or prepared from at least about 150 mL and lessthan about 250 mL of pathogen-inactivated plasma. Individualcryoprecipitates may be combined or pooled after cryoprecipitateproduction but prior to use and/or re-freezing for storage, and/orindividual plasma samples may be combined or pooled prior tocryoprecipitate production.

In some embodiments, a cryoprecipitate may be part of a compositioncontaining plasma at a specific volume. For example, cryoprecipitate istypically resuspended in a volume of plasma remaining aftercryoprecipitate production (e.g., some amount of leftover plasma afterproduction of the cryoprecipitate). This volume may then be used orfrozen for storage as described herein.

In some embodiments, a composition comprising a cryoprecipitate of thepresent disclosure includes plasma (e.g., cryo-poor plasma) of a volumethat is less than about any of the following volumes (in mL): 150, 140,130, 120, 110, 100, 90, 80, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66,65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 45, 40,35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6.In some embodiments, a composition comprising a cryoprecipitate of thepresent disclosure includes plasma of a volume that is greater thanabout any of the following volumes (in mL): 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, or 60. That is, the composition comprising acryoprecipitate of the present disclosure may include plasma of anyvolume within a range having an upper limit of 150, 140, 130, 120, 110,100, 90, 80, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62,61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 45, 40, 35, 30, 25, 20,19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6 mL and anindependently selected lower limit of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, or 60 mL, wherein the upper limit is greater than the lowerlimit. In some embodiments, a composition comprising a cryoprecipitateof the present disclosure includes between about 5 mL and about 25 mL ofplasma, about 5 mL and about 20 mL of plasma, about 10 mL to about 20 mLof plasma, or about 15 mL to about 20 mL of plasma. In otherembodiments, a composition comprising a cryoprecipitate of the presentdisclosure includes between about 30 mL and about 150 mL, between about75 mL and about 150 mL, between about 30 mL and about 75 mL of plasma,between about 40 mL and about 75 mL of plasma, between about 50 mL andabout 75 mL of plasma, between about 60 mL and about 75 mL of plasma,between about 50 mL and about 70 mL of plasma, between about 50 mL andabout 65 mL of plasma, between about 50 mL and about 60 mL of plasma,between about 55 mL to about 70 mL of plasma, between about 55 mL toabout 65 mL of plasma, between about 55 mL to about 60 mL of plasma, orbetween about 60 mL and about 70 mL of plasma. In other embodiments, acomposition comprising a cryoprecipitate of the present disclosureincludes greater than about 1 mL and less than or equal to about 75 mLof plasma, or greater than about 5 mL and less than or equal to about 75mL of plasma. In some embodiments, a composition comprising acryoprecipitate of the present disclosure includes about 10 mL, about 20mL, about 30 mL, about 40 mL, about 50 mL, about 60 mL, about 70 mL,about 80 mL, about 90 mL, about 100 mL, about 110 mL, about 120 mL orabout 130 mL of plasma. In some embodiments, the aforementioned plasmavolumes comprise the plasma volumes following resuspension of thecryoprecipitate.

In some embodiments, the specific volume of plasma may depend upon theamount of cryoprecipitate (e.g., depend upon the amount of plasma usedto produce the cryoprecipitate). In some embodiments, forcryoprecipitate obtained from one AABB unit volume of plasma (e.g., 200mL), the volume of plasma in the composition may be from about 5 mL toabout 25 mL, from about 5 mL to about 20 mL, from about 10 mL to about20 mL or from about 15 mL to about 20 mL, or any other comparable rangeas described above. In some embodiments, for cryoprecipitate obtainedfrom more than one AABB unit volume of plasma (e.g., 550-650 mL), or fora pool of multiple cryoprecipitate preparations (e.g., each having beenobtained from about 200 mL of plasma), the volume of plasma in thecomposition may be from about 15 mL to about 75 mL, from about 15 mL toabout 60 mL, from about 30 mL to about 75 mL, from about 30 mL to about60 mL, from about 30 mL to about 40 mL, 40 mL to about 70 mL, from about45 mL to about 65 mL, from about 50 mL to about 60 mL, or any othercomparable range as described above. In certain embodiments, the volumeof plasma in the composition may be less than or equal to about 75 mL.In some embodiments, for cryoprecipitate obtained by combining two ormore cryoprecipitate preparations, each made from more than one AABBunit volume of plasma (e.g., each being 550-650 mL, for an aggregatetotal of 1100-1300 mL), the volume of plasma in the composition may befrom about 30 mL to about 150 mL, from about 30 mL to about 120 mL, fromabout 60 mL to about 120 mL, from about 90 mL to about 120 mL, fromabout 50 mL to about 100 mL, from about 60 mL to about 90 mL, from about60 mL to about 75 mL from about 50 mL to about 75 mL, or about 75 mL. Incertain embodiments, the volume of plasma in the composition obtained bycombining two or more cryoprecipitate preparations may be less than orequal to about 75 mL.

As described herein and well known in the art, a cryoprecipitate orcryoprecipitate composition or cryo-poor plasma of the presentdisclosure may be tested for the amount and/or activity of one or morecomponents, including without limitation fibrinogen, Factor VIII, FactorXIII, and/or vWF. In some embodiments, this testing refers to ameasurement taken from an individual sample. In other embodiments, itrefers to an average based on measurements taken from multiple samples(e.g., random samples of sufficient number to provide a statisticallysignificant sampling). Often, multiple cryoprecipitate compositions(units) may be thawed during a particular period of production (e.g., 1month of production) and tested to yield a measurement that is held tobe representative of those units that were not tested. Similarly,multiple cryo-poor plasma compositions (units) may be thawed during aparticular period of production (e.g., 1 month of production) and testedto yield a measurement that is held to be representative of those unitsthat were not tested. The un-tested or non-tested samples may then beused in a treatment, such as an infusion. Therefore, “testing” as usedherein refers to testing a particular cryoprecipitate and/or cryo-poorplasma composition, or it refers to testing other cryoprecipitate and/orcryo-poor plasma compositions in a defined cross-section ofcryoprecipitate and/or cryo-poor plasma compositions (e.g., in which ameasurement of one or more individual samples or average of measurementsis held to be representative of a cryoprecipitate and/or cryo-poorplasma composition that was not tested). In some embodiments, acryoprecipitate or cryoprecipitate composition or cryo-poor plasma ofthe present disclosure may be tested prior to re-freezing and/orstorage. In some embodiments, a cryoprecipitate or cryoprecipitatecomposition or cryo-poor plasma of the present disclosure may be testedafter thawing. In some embodiments, a cryoprecipitate or cryoprecipitatecomposition or cryo-poor plasma of the present disclosure may be testedbefore use, e.g., in an infusion. As used herein, the terms “testing”and “determining,” including grammatical derivatives thereof, may beused interchangeably. Therefore, “determining” as used herein refers todetermining an amount of an analyte of interest (including withoutlimitation fibrinogen, Factor VIII, Factor XIII, and/or vWF) in aparticular cryoprecipitate and/or cryo-poor plasma composition, or itrefers to determining an amount of the analyte of interest in othercryoprecipitate and/or cryo-poor plasma compositions in a definedcross-section of cryoprecipitate and/or cryo-poor plasma compositions(e.g., in which a measurement of one or more individual samples oraverage of measurements is held to be representative of acryoprecipitate and/or cryo-poor plasma composition that was not tested,such as a plurality of cryoprecipitate and/or cryo-poor plasmacompositions produced by the same methods and/or produced in the samelocation or general time frame, e.g., within 30 days).

It will be appreciated by one of skill in the art that a cryoprecipitateor cryoprecipitate composition or cryo-poor plasma of the presentdisclosure may be tested at one or more times (e.g., after thawing) forthe amount and/or activity of one or more components, including withoutlimitation fibrinogen, Factor VIII, Factor XIII, and/or vWF. Forexample, a cryoprecipitate or cryoprecipitate composition or cryo-poorplasma of the present disclosure may be tested shortly after thawing(e.g., within 2 hours of thawing, within 6 hours of thawing), and/or acryoprecipitate or cryoprecipitate composition or cryo-poor plasma ofthe present disclosure may be tested at or shortly preceding the time ofinfusion or the time of expiry post-thaw, which, in some embodimentsdescribed herein, may occur up to about 1 day, up to about 2 days, up toabout 3 days, up to about 4 days, up to about 5 days, or up to about 7days after thawing. It is to be understood that any of the exemplaryamounts of cryoprecipitate or cryoprecipitate composition or cryo-poorplasma components described herein (e.g., fibrinogen, Factor VIII,Factor XIII, and/or vWF) refers to an amount tested or determinedshortly after thawing (e.g., within 2 hours of thawing, within 6 hoursof thawing) or an amount tested at or shortly preceding the time ofinfusion or the time of expiry post-thaw (e.g., up to about 1 day, up toabout 2 days, up to about 3 days, up to about 4 days, up to about 5days, or up to about 7 days after thawing).

In some embodiments, a cryoprecipitate or cryoprecipitate composition orcryo-poor plasma of the present disclosure may be tested for FactorVIII. Various assays for measuring Factor VIII are known in the art,including without limitation the chromogenic assay, the one-stageclotting or activated partial thromboplastin time (APTT) assay, and thetwo-stage clotting or activated partial thromboplastin time (APTT)assay. Without wishing to be bound to theory, it is thought thatcryoprecipitate having less than a particular amount of Factor VIII,e.g., an AABB standard for Factor VIII such as 80 IU per unit, mayadvantageously be used for the treatment of many conditions, includingwithout limitation control of bleeding associated with fibrinogendeficiency, treating Factor XIII deficiency, treating von Willebranddisease, maintenance of hemostasis, treating disseminated intravascularcoagulation (DIC) or high volume hemorrhage, and/or making fibrinsealant. Advantageously, this cryoprecipitate, preferably containingpathogen inactivated plasma, may be suitable for infusion after agreater duration post-thawing than, e.g., recommended by current AABBstandards (such as less than 6 hours).

In some embodiments, a cryoprecipitate or cryoprecipitate composition orcryo-poor plasma of the present disclosure contains less than about 80,less than about 75, less than about 70, less than about 65, less thanabout 60, less than about 55, less than about 50, less than about 45,less than about 40, less than about 35, less than about 30, less thanabout 25, less than about 20, less than about 15, or less than about 10IU of Factor VIII per unit of cryoprecipitate (e.g., per unit ofcryoprecipitate derived from about 200 mL of plasma) or cryo-poorplasma. In some embodiments, a composition comprising a cryoprecipitateor cryo-poor plasma of the present disclosure includes Factor VIII at anamount that is less than about any of the following amounts (in IU,either absolute or per unit of cryoprecipitate): 480, 450, 400, 350,300, 250, 225, 200, 175, 150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60,55, 50, 45, 40, 35, 30, 25, 20, or 15. In some embodiments, acomposition comprising a cryoprecipitate or cryo-poor plasma of thepresent disclosure includes Factor VIII at an amount that is greaterthan about any of the following amounts (in IU, either absolute or perunit of cryoprecipitate): 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, or 225. That is,the composition comprising a cryoprecipitate or cryo-poor plasma of thepresent disclosure may include Factor VIII at any amount within a rangehaving an upper limit of 480, 450, 400, 350, 300, 250, 225, 200, 175,150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30,25, 20, or 15 IU and an independently selected lower limit of 10, 15,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,125, 150, 175, 200, or 225 IU, wherein the upper limit is greater thanthe lower limit. In other embodiments, a cryoprecipitate orcryoprecipitate composition of the present disclosure contains at least80 IU of Factor VIII per unit (e.g., 200 mL unit, per unit ofcryoprecipitate derived from about 200 mL of plasma) of cryoprecipitate.In some embodiments, a cryoprecipitate or cryoprecipitate composition ofthe present disclosure contains at least 80 IU of Factor VIII. In someembodiments, a cryoprecipitate or cryoprecipitate composition of thepresent disclosure contains 80-100 IU of Factor VIII per unit (e.g., 200mL unit, per unit of cryoprecipitate derived from about 200 mL ofplasma) of cryoprecipitate. Factor VIII content of a cryoprecipitate orcryoprecipitate composition of the present disclosure may be expressedper unit volume (e.g., per unit of cryoprecipitate derived from about200 mL of plasma), or as an absolute amount. In some embodiments, acryoprecipitate or cryoprecipitate composition of the present disclosurecontains less than about 80 IU or less than about 50 IU of Factor VIIIper unit (e.g., 200 mL unit, per unit of cryoprecipitate derived fromabout 200 mL of plasma) of cryoprecipitate at the time of thawing (e.g.,within about 1 hour or within about 2 hours of thawing). In someembodiments, a cryoprecipitate or cryoprecipitate composition of thepresent disclosure contains less than about 80 IU or less than about 50IU of Factor VIII per unit of cryoprecipitate at or shortly precedingthe infusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing). In some embodiments, acryoprecipitate or cryoprecipitate composition of the present disclosurecontains less than about 80 IU of Factor VIII at or shortly precedingthe infusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing). In some embodiments, acryoprecipitate or cryoprecipitate composition of the present disclosurecontains at least about 80 IU of Factor VIII at or shortly preceding theinfusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing). In some embodiments, acryoprecipitate or cryoprecipitate composition of the present disclosurecontains 80-100 IU of Factor VIII at or shortly preceding the infusion(e.g., up to about 1 day, up to about 3 days, up to about 5 days, or upto about 7 days after thawing). In some embodiments, a cryoprecipitateor cryoprecipitate composition of the present disclosure containscomprises about 80-240 IU (e.g., total IU) of Factor VIII at or shortlypreceding the infusion (e.g., up to about 1 day, up to about 3 days, upto about 5 days, or up to about 7 days after thawing). In someembodiments, a cryoprecipitate or cryoprecipitate composition of thepresent disclosure contains comprises about 80-480 IU (e.g., total IU)of Factor VIII at or shortly preceding the infusion (e.g., up to about 1day, up to about 3 days, up to about 5 days, or up to about 7 days afterthawing). In some embodiments, an amount of factor VIII is determinedfrom cryoprecipitate sampled within about 2 hours, within about 6 hours,within about 1 day, within about 2 days, within about 3 days, withinabout 4 days, or within about 5 days after thawing.

In some embodiments, a composition contains cryoprecipitate preparedfrom at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma. In some embodiments, a composition containstwo or more cryoprecipitates, each of the two or more cryoprecipitatesprepared from at least about 150 mL and less than about 250 mL ofplasma, e.g., about 200 mL of plasma. In some embodiments,cryoprecipitate prepared from at least about 550 mL and less than about650 mL of pathogen-inactivated plasma contains between about 80 andabout 200 IU of Factor VIII, e.g., at or shortly preceding the infusion(e.g., up to about 1 day, up to about 3 days, up to about 5 days, or upto about 7 days after thawing). For example, in some embodiments,cryoprecipitate prepared from at least about 550 mL and less than about650 mL of pathogen-inactivated plasma contains between about 80 andabout 200 IU of Factor VIII at the time of thawing (e.g., within about 1hour or within about 2 hours of thawing). In some embodiments,cryoprecipitate prepared from at least about 550 mL and less than about650 mL of pathogen-inactivated plasma contains between about 80 andabout 200 IU of Factor VIII as determined within about 2 hours, withinabout 6 hours, within about 1 day, within about 2 days, within about 3days, within about 4 days, or within about 5 days after thawing.

In some embodiments, a composition contains a first cryoprecipitateprepared from at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma and a second cryoprecipitate prepared fromat least about 550 mL and less than about 650 mL of pathogen-inactivatedplasma. In some embodiments, a composition containing twocryoprecipitates, each prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma, contains between about 160and about 400 IU of Factor VIII, e.g., at or shortly preceding theinfusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing). For example, in someembodiments, a composition containing two cryoprecipitates, eachprepared from at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma, contains between about 160 and about 400 IUof Factor VIII at the time of thawing (e.g., within about 1 hour orwithin about 2 hours of thawing). In some embodiments, a compositioncontaining two cryoprecipitates, each prepared from at least about 550mL and less than about 650 mL of pathogen-inactivated plasma, containsbetween about 160 and about 400 IU of Factor VIII as determined withinabout 2 hours, within about 6 hours, within about 1 day, within about 2days, within about 3 days, within about 4 days, or within about 5 daysafter thawing.

In some embodiments, a cryoprecipitate or cryoprecipitate composition orcryo-poor plasma of the present disclosure may be tested for fibrinogen.Various assays for measuring fibrinogen are known in the art, includingwithout limitation the Clauss method, prothrombin time-derived assays,immunological assays, and gravimetric assays. In some embodiments, acryoprecipitate or cryoprecipitate composition or cryo-poor plasma ofthe present disclosure contains an amount of fibrinogen meeting AABBstandards. In some embodiments, a cryoprecipitate or cryoprecipitatecomposition or cryo-poor plasma of the present disclosure contains atleast about 100, at least about 150, at least about 200, at least about250, or at least about 300 mg of fibrinogen per unit of cryoprecipitate(e.g., per unit of cryoprecipitate derived from about 200 mL of plasma).In some embodiments, a composition comprising a cryoprecipitate orcryo-poor plasma of the present disclosure includes fibrinogen at anamount that is less than about any of the following amounts (in mg,either absolute or per unit of cryoprecipitate): 2500, 2000, 1800, 1500,1200, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, or150. In some embodiments, a composition comprising a cryoprecipitate orcryo-poor plasma of the present disclosure includes fibrinogen at anamount that is greater than about any of the following amounts (in mg,either absolute or per unit of cryoprecipitate): 140, 150, 200, 250,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000,1100, 1200, or 1500. That is, the composition comprising acryoprecipitate or cryo-poor plasma of the present disclosure mayinclude fibrinogen at any amount within a range having an upper limit of2500, 2000, 1800, 1500, 1200, 750, 700, 650, 600, 550, 500, 450, 400,350, 300, 250, 200, or 150 mg and an independently selected lower limitof 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 140,150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,850, 900, 1000, 1100, 1200, or 1500 mg, wherein the upper limit isgreater than the lower limit. In some embodiments, a cryoprecipitate orcryoprecipitate composition or cryo-poor plasma of the presentdisclosure contains at least about 250 mg or at least about 150 mg offibrinogen per unit of cryoprecipitate (e.g., per unit ofcryoprecipitate derived from about 200 mL of plasma) or cryo-poor plasmaat the time of thawing (e.g., within about 1 hour or within about 2hours of thawing). In some embodiments, a cryoprecipitate orcryoprecipitate composition or cryo-poor plasma of the presentdisclosure contains at least about 250 mg or at least about 150 mg offibrinogen per unit of cryoprecipitate (e.g., per unit ofcryoprecipitate derived from about 200 mL of plasma) or cryo-poor plasmaat or shortly preceding the infusion (e.g., up to about 1 day, up toabout 3 days, up to about 5 days, or up to about 7 days after thawing).In some embodiments, a cryoprecipitate or cryoprecipitate composition orcryo-poor plasma of the present disclosure contains at least about 250mg or at least about 150 mg of fibrinogen at the time of thawing (e.g.,within about 1 hour or within about 2 hours of thawing). In someembodiments, a cryoprecipitate or cryoprecipitate composition orcryo-poor plasma of the present disclosure contains at least about 750mg of fibrinogen (e.g., total mg of fibrinogen) at or shortly precedingthe infusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing). In some embodiments, acryoprecipitate or cryoprecipitate composition or cryo-poor plasma ofthe present disclosure contains at least about 750 mg of fibrinogen(e.g., total mg of fibrinogen) at the time of thawing (e.g., withinabout 1 hour or within about 2 hours of thawing). In some embodiments,an amount of fibrinogen is determined from cryoprecipitate sampledwithin about 2 hours, within about 6 hours, within about 1 day, withinabout 2 days, within about 3 days, within about 4 days, or within about5 days after thawing.

In some embodiments, a composition contains cryoprecipitate preparedfrom at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma. In some embodiments, a composition containstwo or more cryoprecipitates, each of the two or more cryoprecipitatesprepared from at least about 150 mL and less than about 250 mL ofplasma, e.g., about 200 mL of plasma. In some embodiments,cryoprecipitate prepared from at least about 550 mL and less than about650 mL of pathogen-inactivated plasma contains between about 700 mg andabout 1000 mg of fibrinogen, e.g., at or shortly preceding the infusion(e.g., up to about 1 day, up to about 3 days, up to about 5 days, or upto about 7 days after thawing). For example, in some embodiments,cryoprecipitate prepared from at least about 550 mL and less than about650 mL of pathogen-inactivated plasma contains between about 700 mg andabout 1000 mg of fibrinogen at the time of thawing (e.g., within about 1hour or within about 2 hours of thawing). In some embodiments,cryoprecipitate prepared from at least about 550 mL and less than about650 mL of pathogen-inactivated plasma contains between about 700 mg andabout 1000 mg of fibrinogen as determined within about 2 hours, withinabout 6 hours, within about 1 day, within about 2 days, within about 3days, within about 4 days, or within about 5 days after thawing.

In some embodiments, a composition contains a first cryoprecipitateprepared from at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma and a second cryoprecipitate prepared fromat least about 550 mL and less than about 650 mL of pathogen-inactivatedplasma. In some embodiments, a composition containing twocryoprecipitates, each prepared from at least about 550 mL and less thanabout 650 mL of pathogen-inactivated plasma, contains between about 1400mg and about 2000 mg of fibrinogen, e.g., at or shortly preceding theinfusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing). For example, in someembodiments, a composition containing two cryoprecipitates, eachprepared from at least about 550 mL and less than about 650 mL ofpathogen-inactivated plasma, contains between about 1400 mg and about2000 mg of fibrinogen at the time of thawing (e.g., within about 1 houror within about 2 hours of thawing). In some embodiments, a compositioncontaining two cryoprecipitates, each prepared from at least about 550mL and less than about 650 mL of pathogen-inactivated plasma, containsbetween about 1400 mg and about 2000 mg of fibrinogen as determinedwithin about 2 hours, within about 6 hours, within about 1 day, withinabout 2 days, within about 3 days, within about 4 days, or within about5 days after thawing.

In some embodiments, a cryoprecipitate or cryoprecipitate composition ofthe present disclosure may be tested for vWF. Various assays formeasuring vWF (such as vWF:RCo and vWF:Ag assays) are known in the art,including without limitation vWF ELISA, platelet agglutination, flowcytometry, and latex immunoassays. In some embodiments, acryoprecipitate or cryoprecipitate composition of the present disclosurecontains an amount of vWF meeting AABB standards. In some embodiments, acryoprecipitate or cryoprecipitate composition of the present disclosurecontains at least about 80, at least about 90, at least about 100, atleast about 110, at least about 120, at least about 130, at least about140, or at least about 150 IU of vWF per unit of cryoprecipitate (e.g.,per unit of cryoprecipitate derived from about 200 mL of plasma). Insome embodiments, a composition comprising a cryoprecipitate of thepresent disclosure includes vWF at an amount that is less than about anyof the following amounts (in IU, either absolute or per unit ofcryoprecipitate): 450, 400, 350, 300, 250, 200, 150, 140, 130, 120, 110,100, or 90. In some embodiments, a composition comprising acryoprecipitate of the present disclosure includes vWF at an amount thatis greater than about any of the following amounts (in IU, eitherabsolute or per unit of cryoprecipitate): 80, 90, 100, 110, 120, 130,140, 150, 200, 250, 300, 350, or 400. That is, the compositioncomprising a cryoprecipitate of the present disclosure may include vWFat any amount within a range having an upper limit of 450, 400, 350,300, 250, 200, 150, 140, 130, 120, 110, 100, or 90 IU and anindependently selected lower limit of 80, 90, 100, 110, 120, 130, 140,150, 200, 250, 300, 350, or 400 IU, wherein the upper limit is greaterthan the lower limit. In some embodiments, a cryoprecipitate orcryoprecipitate composition of the present disclosure contains at leastabout 100 IU or at least about 150 IU of vWF per unit of cryoprecipitateat the time of thawing (e.g., within about 1 hour or within about 2hours of thawing). In some embodiments, a cryoprecipitate orcryoprecipitate composition of the present disclosure contains at leastabout 100 IU or at least about 150 IU of vWF per unit of cryoprecipitateat or shortly preceding the infusion (e.g., up to about 1 day, up toabout 3 days, up to about 5 days, or up to about 7 days after thawing).

In some embodiments, a cryoprecipitate or cryoprecipitate composition ofthe present disclosure may be tested for Factor XIII. Various assays formeasuring Factor XIII are known in the art, including without limitationthe Berichrom assay, the clot solubility assay, and a Factor XIII ELISA.In some embodiments, a cryoprecipitate or cryoprecipitate composition ofthe present disclosure contains an amount of Factor XIII meeting AABBstandards. In some embodiments, a cryoprecipitate or cryoprecipitatecomposition of the present disclosure contains at least about 40, atleast about 50, at least about 60, at least about 70, at least about 80,at least about 90, or at least about 100 IU of Factor XIII per unit ofcryoprecipitate (e.g., per unit of cryoprecipitate derived from about200 mL of plasma). In some embodiments, a composition comprising acryoprecipitate of the present disclosure includes Factor XIII at anamount that is less than about any of the following amounts (in IU,either absolute or per unit of cryoprecipitate): 300, 275, 250, 225,200, 175, 150, 125, 100, 90, 80, 70, 60, or 50. In some embodiments, acomposition comprising a cryoprecipitate of the present disclosureincludes Factor XIII at an amount that is greater than about any of thefollowing amounts (in IU, either absolute or per unit ofcryoprecipitate): 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225,250, or 275. That is, the composition comprising a cryoprecipitate ofthe present disclosure may include Factor XIII at any amount within arange having an upper limit of 300, 275, 250, 225, 200, 175, 150, 125,100, 90, 80, 70, 60, or 50 IU and an independently selected lower limitof 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, or 275 IU,wherein the upper limit is greater than the lower limit. In someembodiments, a cryoprecipitate or cryoprecipitate composition of thepresent disclosure contains at least about 100 IU or at least about 150IU of Factor XIII per unit of cryoprecipitate at the time of thawing(e.g., within about 1 hour or within about 2 hours of thawing). In someembodiments, a cryoprecipitate or cryoprecipitate composition of thepresent disclosure contains at least about 100 IU or at least about 150IU of Factor XIII per unit of cryoprecipitate at or shortly precedingthe infusion (e.g., up to about 1 day, up to about 3 days, up to about 5days, or up to about 7 days after thawing).

Any of the above amounts of cryoprecipitate or cryo-poor plasmacomponents may be combined in any number or combination describedherein. For example, in some embodiments, a cryoprecipitate orcryoprecipitate composition or cryo-poor plasma of the presentdisclosure contains less than about 80 IU or less than about 50 IU ofFactor VIII per unit of cryoprecipitate or cryo-poor plasma and at leastabout 250 mg or at least about 150 mg of fibrinogen per unit ofcryoprecipitate or cryo-poor plasma at the time of thawing (e.g., withinabout 1 hour or within about 2 hours of thawing). In some embodiments, acryoprecipitate or cryoprecipitate composition or cryo-poor plasma ofthe present disclosure contains less than about 80 IU or less than about50 IU of Factor VIII per unit of cryoprecipitate or cryo-poor plasma andat least about 250 mg or at least about 150 mg of fibrinogen per unit ofcryoprecipitate or cryo-poor plasma at or shortly preceding the infusion(e.g., up to about 1 day, up to about 3 days, up to about 5 days, or upto about 7 days after thawing).

In some embodiments, a cryoprecipitate, cryoprecipitate composition,and/or cryo-poor plasma of the present disclosure may be prepared fromplasma other than group O plasma, e.g., group A, B, and/or AB plasma. Insome embodiments, a cryoprecipitate, cryoprecipitate composition, and/orcryo-poor plasma of the present disclosure may be prepared from plasmaof more than one ABO type. In some embodiments, a cryoprecipitate,cryoprecipitate composition, and/or cryo-poor plasma of the presentdisclosure may be prepared from A, B, and AB type plasma.

In some embodiments, a cryoprecipitate, cryoprecipitate composition,and/or cryo-poor plasma of the present disclosure may be contained in acontainer of the present disclosure. In some embodiments, the containerfurther comprises a label indicating that the composition is suitablefor use (e.g., suitable for infusion) for up to about 1 day, 2 days, 3days, 4 days, 5 days, 6 days, or 7 days after thawing.

Further provided herein is a cryoprecipitate produced by any of themethods of the present disclosure, e.g., including one or more of theaspects and features described above in any order or combination.

Cryoprecipitate and/or Cryo-Poor Plasma Kits or Articles of Manufacture

In some embodiments, a cryoprecipitate, cryoprecipitate composition,and/or cryo-poor plasma of the present disclosure, or one produced bythe methods of the present disclosure, may be packaged in a kit orarticle of manufacture. In some embodiments, a kit or article ofmanufacture may include a container, a pathogen-inactivatedcryoprecipitate and/or cryo-poor plasma, and instructions for using thepathogen-inactivated cryoprecipitate and/or cryo-poor plasma. In someembodiments, a kit or article of manufacture may include a container, apathogen-inactivated cryoprecipitate and/or cryo-poor plasma, and alabel indicating that the pathogen-inactivated cryoprecipitate and/orcryo-poor plasma is suitable for use for up to about 1 day, up to about2 days, up to about 3 days, up to about 4 days, up to about 5 days, upto about 6 days, or up to about 7 days after thawing. In someembodiments, a kit or article of manufacture may further include anyother material or device useful in a treatment (e.g., a transfusion),including without limitation one or more containers, tubing, sterilizingagents or equipment, cannulae, syringes, and the like.

In some embodiments, the instructions may be for using thepathogen-inactivated cryoprecipitate and/or cryo-poor plasma in aninfusion into a subject. In some embodiments, the instructions mayindicate an expiry date of the cryoprecipitate and/or cryo-poor plasma,e.g., a date by which the cryoprecipitate and/or cryo-poor plasma shouldbe used in a treatment (e.g., an infusion) after thawing. In someembodiments, the instructions may indicate that the cryoprecipitateand/or cryo-poor plasma is suitable for infusion into the subject for upto about 1 day, up to about 2 days, up to about 3 days, up to about 4days, up to about 5 days, up to about 6 days, or up to about 7 daysafter thawing. In some embodiments, the instructions may indicate thatthe cryoprecipitate and/or cryo-poor plasma is suitable for infusioninto the subject for up to about 6 hours, up to about 12 hours, up toabout 24 hours, up to about 36 hours, up to about 48 hours, up to about60 hours, up to about 72 hours, up to about 84 hours, up to about 96hours, up to about 108 hours, up to about 120 hours, up to about 132hours, up to about 144 hours, up to about 156 hours, or up to about 168hours after thawing.

Cryoprecipitate and/or Cryo-Poor Plasma Methods

Certain aspects of the present disclosure relate to methods of preparinga cryoprecipitate and/or cryo-poor plasma for infusion into a subject.Certain aspects of the present disclosure relate to methods of infusinga cryoprecipitate and/or cryo-poor plasma into a subject. It is to beunderstood that any of the cryoprecipitate, cryoprecipitatecompositions, and/or cryo-poor plasma of the present disclosure may finduse in any of the methods described herein. It is to be understood thatany of the features or aspects of cryoprecipitate, cryoprecipitatecompositions, and/or cryo-poor plasma of the present disclosuredescribed herein may find use in any of the methods described herein inany combination.

In some embodiments, the methods of preparing a cryoprecipitate and/orcryo-poor plasma for infusion into a subject and/or methods of infusinga cryoprecipitate and/or cryo-poor plasma into a subject may includepreparing a cryoprecipitate, cryoprecipitate composition, and/orcryo-poor plasma of the present disclosure from pathogen-inactivatedplasma. Any of the exemplary methods of preparing a cryoprecipitateand/or cryo-poor plasma from plasma (e.g., pathogen-inactivated plasma)described herein (e.g., supra), or any methods of preparing acryoprecipitate and/or cryo-poor plasma from plasma known in the art,may be used. Any of the exemplary methods of pathogen inactivatingplasma described herein (e.g., infra), or any methods of pathogeninactivating plasma known in the art, may be used to generate thepathogen-inactivated plasma.

In some embodiments, the methods of preparing a cryoprecipitate and/orcryo-poor plasma for infusion into a subject and/or methods of infusinga cryoprecipitate and/or cryo-poor plasma into a subject may includefreezing a cryoprecipitate, cryoprecipitate composition, and/orcryo-poor plasma of the present disclosure, e.g., as described supra oras is known in the art.

In some embodiments, the methods of preparing a cryoprecipitate and/orcryo-poor plasma for infusion into a subject and/or methods of infusinga cryoprecipitate and/or cryo-poor plasma into a subject may includethawing a frozen cryoprecipitate, cryoprecipitate composition, and/orcryo-poor plasma of the present disclosure, e.g., as described supra oras is known in the art. In some embodiments, the thawed cryoprecipitate,cryoprecipitate composition, and/or cryo-poor plasma may be suitable forinfusion into a subject as described herein for at least about 1 day, atleast about 2 days, at least about 3 days, at least about 4 days, atleast about 5 days, at least about 6 days, or at least about 7 daysafter thawing. In some embodiments, the thawed cryoprecipitate,cryoprecipitate composition, and/or cryo-poor plasma may be suitable forinfusion into a subject as described herein for at least about 6 hours,at least about 12 hours, at least about 24 hours, at least about 36hours, at least about 48 hours, at least about 60 hours, at least about72 hours, at least about 84 hours, at least about 96 hours, at leastabout 108 hours, at least about 120 hours, at least about 132 hours, atleast about 144 hours, at least about 156 hours, or at least about 168hours after thawing.

In some embodiments, the methods of preparing a cryoprecipitate forinfusion into a subject and/or methods of infusing a cryoprecipitateinto a subject may include testing the thawed cryoprecipitate (e.g.,testing one or more representative random cryoprecipitate preparations)for Factor VIII, e.g., as described herein or known in the art. In someembodiments, the thawed cryoprecipitate may be tested for Factor VIIIprior to infusion. In some embodiments, the thawed cryoprecipitate mayhave been tested for Factor VIII prior to freezing. In otherembodiments, the methods of preparing a cryoprecipitate for infusioninto a subject and/or methods of infusing a cryoprecipitate into asubject may exclude testing the thawed cryoprecipitate for Factor VIII.In some embodiments, the methods of preparing a cryoprecipitate forinfusion into a subject and/or methods of infusing a cryoprecipitateinto a subject may include testing the thawed cryoprecipitate forfibrinogen, but exclude testing for Factor VIII.

In some embodiments, the methods of preparing a cryoprecipitate forinfusion into a subject and/or methods of infusing a cryoprecipitateinto a subject may include testing the thawed cryoprecipitate (e.g.,testing one or more representative random cryoprecipitate preparations)for fibrinogen, e.g., as described herein or known in the art. In someembodiments, the thawed cryoprecipitate may be tested for fibrinogenprior to infusion. In some embodiments, the thawed cryoprecipitate mayhave been tested for fibrinogen prior to freezing. In other embodiments,the methods of preparing a cryoprecipitate for infusion into a subjectand/or methods of infusing a cryoprecipitate into a subject may excludetesting the thawed cryoprecipitate for fibrinogen.

In some embodiments, the methods of preparing a cryoprecipitate and/orcryo-poor plasma for infusion into a subject and/or methods of infusinga cryoprecipitate and/or cryo-poor plasma into a subject may include acryoprecipitate and/or cryo-poor plasma made from about 600 mL ofpathogen-inactivated plasma, from at least about 550 mL and less than650 mL of pathogen-inactivated plasma, from at least about 570 mL andless than 620 mL of pathogen-inactivated plasma, or from at least about600 mL and less than 650 mL of pathogen-inactivated plasma. Such acryoprecipitate and/or cryo-poor plasma may be obtained, e.g., frompooling multiple unit volumes of plasma (e.g., 200 mL unit volumes, AABBunit volumes, to yield 550-650 mL), or from pooling multiplecryoprecipitates and/or cryo-poor plasma obtained from different samplesof plasma. Individual cryoprecipitates and/or cryo-poor plasma may becombined or pooled after cryoprecipitate/cryo-poor plasma production butprior to re-freezing for storage, and/or individual plasma samples maybe combined or pooled prior to use, storage at room temperature or underrefrigeration, and/or cryoprecipitate production. In some embodiments,two or more cryoprecipitates and/or cryo-poor plasma may be combinedprior to using, storing, and/or freezing the cryoprecipitate and/orcryo-poor plasma. In some embodiments, two or more cryoprecipitatesand/or cryo-poor plasma may be combined after freezing thecryoprecipitate and/or cryo-poor plasma but prior to infusion.

In some embodiments, the methods of the present disclosure may furthercomprise infusing a cryoprecipitate or cryoprecipitate composition ofthe present disclosure into a subject. Methods of infusing acryoprecipitate into a subject are well known in the art. In someembodiments, the cryoprecipitate may be infused at a rate of about 1 mL,about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL,about 8 mL, about 9 mL, or about 10 mL per minute, or for a totalduration of about 30 minutes to about 4 hours. In some embodiments, apool of cryoprecipitates (e.g., equivalent to 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 units) may be infused. In some embodiments, the infusionis sufficient to raise the subject's fibrinogen level by an amount fromabout 30 mg/dL to about 60 mg/dL, e.g., by about 40 mg/dL. In someembodiments, the infusion is a transfusion. Further description ofcryoprecipitate infusion dosing, response, indications, and preparationmay be found, e.g., in the American Red Cross Compendium of TransfusionPractice Guidelines, the disclosure of which is hereby incorporated byreference as it relates to cryoprecipitate infusion dosing, response,indications, and preparation.

Further disclosed herein are methods for preparing a cryoprecipitateand/or cryo-poor plasma for infusion into a subject. In someembodiments, the methods include preparing a cryoprecipitate and/orcryo-poor plasma from pathogen-inactivated plasma (e.g., as describedherein) and freezing the cryoprecipitate and/or cryo-poor plasma. Insome embodiments, the methods include preparing a cryoprecipitate aand/or cryo-poor plasma, respectively, from pathogen-inactivated plasma(e.g., as described herein) and storing the cryoprecipitate and/orcryo-poor plasma at room temperature or under refrigeration before usingin an infusion. In some embodiments, the cryoprecipitate and/orcryo-poor plasma, respectively, is suitable for infusion into thesubject for up to about 1 day, 2 days, 3 days, 4 days, 5 days 6 days, or7 days after thawing, as described herein. In some embodiments, thecryoprecipitate and/or cryo-poor plasma is prepared from at least about550 mL and less than about 650 mL of pathogen-inactivated plasma of thepresent disclosure. In certain embodiments, the cryoprecipitate and/orcryo-poor plasma is prepared from about 600 mL of pathogen-inactivatedplasma of the present disclosure.

In some embodiments, the methods further include combining a firstcryoprecipitate and/or cryo-poor plasma, respectively, prepared from atleast about 150 mL and less than about 250 mL (e.g., about 200 mL) ofpathogen-inactivated plasma of the present disclosure and a secondcryoprecipitate and/or cryo-poor plasma, respectively, prepared from atleast about 150 mL and less than about 250 mL (e.g., about 200 mL) ofpathogen-inactivated plasma of the present disclosure. In someembodiments, the methods further include combining a firstcryoprecipitate and/or cryo-poor plasma, respectively, prepared from atleast about 550 mL and less than about 650 mL of pathogen-inactivatedplasma of the present disclosure and a second cryoprecipitate and/orcryo-poor plasma, respectively, prepared from at least about 550 mL andless than about 650 mL of pathogen-inactivated plasma of the presentdisclosure. In some embodiments, the first and the secondcryoprecipitates and/or cryo-poor plasma, respectively, are combinedprior to freezing the cryoprecipitate and/or cryo-poor plasma. Incertain embodiments, the first cryoprecipitate and/or cryo-poor plasma,respectively, is prepared from about 600 mL of pathogen-inactivatedplasma of the present disclosure, and the second cryoprecipitate and/orcryo-poor plasma, respectively, is prepared from about 600 mL ofpathogen-inactivated plasma of the present disclosure.

In some embodiments, the methods further include combining a firstcryoprecipitate and/or cryo-poor plasma, respectively, prepared orobtained from 1-3 (e.g., 3) units of pathogen-inactivated plasma of thepresent disclosure and a second cryoprecipitate and/or cryo-poor plasma,respectively, prepared or obtained from 1-3 (e.g., 3) units ofpathogen-inactivated plasma of the present disclosure. In someembodiments, the first and the second cryoprecipitates and/or cryo-poorplasma are combined prior to freezing the cryoprecipitate.

In any of the methods of the present disclosure, the subject may be ahuman. In other embodiments, the subject may be a veterinary subject.

Cryoprecipitate and/or Cryo-Poor Plasma Processing

Cryoprecipitate and/or cryo-poor plasma processing and the handling ofblood products typically involves the use of blood compatible bagsystems, which are well known in the art, as described, for example, inU.S. Pat. Nos. 5,405,343, 7,025,877, and 8,439,889, the disclosures ofwhich are incorporated by reference herein for the disclosure of bloodhandling bags and systems. In general, a blood handling system includesmore than one plastic container, typically plastic bags, where the bagsare integrally connected with plastic tubing. Some of the containersdescribed herein include such plastic bags as are known in the storageand handling of blood products, including cryoprecipitates. Bloodhandling bags typically can be designed to hold various volumes offluid, including, but not limited to, volumes ranging from 50 mL to 2liters, for example having up to a 1 liter capacity, up to a 1.5 litercapacity, or up to a 2 liter capacity. Examples of commonblood-collection bags include such bags with volumes of 350 mL, 450 mLand 500 mL, among others. It is understood that when a method refers toa bag, it includes any such plastic bags used in blood handling. Wheresuch bags are referred to as “removal bag”, “product bag”, “transferbag”, “collection bag,” or “illumination bag”, it is understood thatthese bags are typical blood handling bags, or are similar to such bagsin nature. Plastic bags suitable for use according to the presentdisclosure include for example, those comprising PL2410, as well asother suitable plastics known in the art. Plastic bag materials includepolyvinyl chloride, polyolefins, ethylene vinyl acetate, ethylene vinylacetate blended with other plastics, and the like.

As described herein, where tubing is described as connecting e.g. twobags of a processing set, it is understood that the tubing may be joinedat some point therebetween by another component of the connectionbetween the two bags. For example, a removal bag connected to a productbag by tubing includes wherein the tubing comprises a filter between thetwo bags, i.e. the tubing is divided by a filter such that fluid flowsfrom one bag to the other through the tubing and filter. In one example,tubing connecting a removal bag and a product bag can include a filterto remove any loose particles from fluid flowing from the removal deviceto the product bag, i.e. the tubing is divided by, or interrupted by thefilter between the bags. Such filters are designed to remove any smallparticles that may come off of the removal device, while allowingplatelets to pass through the filter. The tubing between bags allows forfluid to flow from one bag to another, which can be blocked to preventthe flow until necessary, e.g. as part of the processing the fluid inone bag may be prevented from flowing to the next bag until required forthe next step in a process. As such an openable seal, such as a clamp,plug, valve or the like is included in or on the tubing connecting thebags, where the clamp, plug, valve or the like can be selectively openedas required, for example to transfer the fluid from one bag to the next.In certain preferred embodiments, the tubing between bags comprises abreakable seal, such as a breakable valve, whereupon breaking thebreakable seal allows for the blood solution to flow between the bagsthrough the tubing. It is understood that the breakable seal iscontained within the connection between containers, such that sterilityof the system is maintained. It is also understood that a tubingcomprising a filter, or a breakable seal, includes where the tubing maybe interrupted by the filter or the seal, for example the tubing runsfrom one bag and is connected to the filter or seal (an incoming portionof the tubing), and the tubing continues from another portion of thefilter or seal to another bag (an outgoing portion of the tubing). Insuch a configuration, fluid flows from the first bag, through theincoming portion of the tubing, through the filter or seal, and throughthe outgoing portion of the tubing and into the other bag.

Different bags within a blood bag system can be used for different stepsof a process. For example, a system of bags to be used for the pathogeninactivation of a unit of cryoprecipitate or plasma can include acontainer with pathogen inactivation compound contained within, a bagfor receiving the unit of cryoprecipitate or plasma and a pathogeninactivation compound (e.g. an illumination bag), a bag for theillumination of the unit of cryoprecipitate or plasma when the pathogeninactivation method includes illumination (e.g., an illumination bag,and typically the same bag to receive the unit of cryoprecipitate orplasma and pathogen inactivation compound), a bag for the removal ofpathogen inactivation compounds and/or by-products thereof from thetreated unit of cryoprecipitate or plasma (e.g., referred to as aremoval bag), and one or more bags for containing the finalcryoprecipitate or plasma product, i.e. the pathogen inactivatedcryoprecipitate or plasma unit that has the concentration of theinactivation compound and/or by-products thereof reduced to below adesired concentration, which is ready for use, can be stored for lateruse (e.g., referred to as a product bag), or in the case of plasma canbe used to generate a cryoprecipitate. Each bag in the system istypically made up of a plastic material. For example, the container forcontaining a solution of pathogen inactivation compound can be made of asuitable plastic such as PL2411 (Baxter Healthcare), or other plasticssuch as polyvinyl chloride, polyolefins, ethylene vinyl acetate,ethylene vinyl acetate blended with other plastics, and the like. Thiscontainer is also overwrapped with a material that is impermeable tolight of a wavelength that will activate the photoactive pathogeninactivation compound (for example suitable plastic such as PL2420,Baxter Healthcare). The illumination bag for a photoactivated pathogeninactivation compound requires a clear, durable thermoplastic materialthat is translucent to light of the selected wavelength. Suitableplastics that are translucent to light in the UVA wavelength rangeinclude polyvinyl chloride, polyolefins, ethylene vinyl acetate,ethylene vinyl acetate blended with other plastics, or other blends ofthermoplastic polymers. Such suitable plastics include PL2410 (BaxterHealthcare) and PL732 (Baxter Healthcare). Similar materials may be usedto make the removal bag and the product bag. The product bags includethose made of PL2410. Suitable bag materials are discussed, for example,in PCT publication number WO 2003078023, and U.S. Pat. No. 7,025,877,the disclosures of which are hereby incorporated by reference as itrelates to such bag materials and related materials. In all cases, thematerials used in preparing the processing set have to be sterilizableby known methods such as steam and gamma or electron beam radiation usedto ensure sterility of the processing set. While these are exemplarymaterials for making the bags, the methods described herein areapplicable to processes using any suitable bag material as would bereadily available to one skilled in the art, and can also be used withcontainers other than bags. The bags used for illumination, removal, andstorage are also designed to allow for gases such as oxygen and carbondioxide to go into and out of the blood bag, so that the blood productstherein have adequate oxygen supply and carbon dioxide levels during theprocessing and storage.

Pathogen Inactivation

Blood products, including cryoprecipitate, cryo-poor plasma, or plasmablood products such frozen plasma (e.g., FFP, PF24), may containpathogens, or may be contaminated with pathogens during processing. Assuch, it is desirable to subject such blood products to a process inorder to reduce the risk of transfusion-transmitted diseases. In someembodiments, plasma may be subjected to one or more treatments toinactivate pathogens (i.e., pathogen inactivation, pathogen reduction).In some embodiments, the pathogen-inactivated plasma may then be used toproduce a cryoprecipitate and a cryo-poor plasma, as described herein.In some embodiments, cryoprecipitate and/or cryo-poor plasma may besubjected to one or more treatments to inactivate pathogens (i.e.,pathogen inactivation, pathogen reduction).

Various methods are available to mitigate the risk oftransfusion-associated disease transmission in cryoprecipitate,cryo-poor plasma or plasma-containing blood products. Aside fromscreening and detection of pathogens and subsequent elimination ofcontaminated blood products, processes that incorporate treatments toinactivate pathogens (i.e., pathogen inactivation, pathogen reduction)that may be present are available. Ideally, such a process results inthe inactivation of a broad range of pathogens such as viruses, bacteriaand parasites that may be present in the blood product. In certainembodiments, the method of pathogen inactivation is based on asolvent/detergent process to treat plasma (OCTAPLAS, Octapharma; Solheimet al., 2000, Transfusion, 40:84-90). In certain embodiments, the methodof pathogen inactivation is a methylene blue process to treat plasma(THERAFLEX-MB, MacoPharma; Garwood et al., 2003, Transfusion43:1238-1247). In certain embodiments, the method of pathogeninactivation is based on a riboflavin/UV light process to treat plasma(MIRASOL, TerumoBCT; Hornsey et al., 2009, Transfusion 49:2167-2172). Incertain embodiments, the method of pathogen inactivation requiresaddition of an amount of pathogen inactivation compound to a unit ofcryoprecipitate or plasma. For example, pathogen inactivation mayinvolve the addition of a low molecular weight compound, such as forexample a psoralen (e.g., amotosalen) that inactivates various pathogens(INTERCEPT Blood System, Cerus Corporation; Mintz et al., 2006,Transfusion 46:1693-1704).

In some embodiments, pathogen inactivation may involve photochemicalinactivation (e.g., photoinactivation), which involves the addition of aphotosensitizer that, when activated by illumination using light ofsuitable wavelengths, will inactivate a variety of pathogens that may bepresent. Two such methods include the addition of amotosalen orriboflavin to the blood product, with subsequent illumination with UVlight. Other methods include illumination with UV light without additionof a photosensitizer, as well as illumination with other photoactivecompounds, including psoralen derivatives other than amotosalen,isoalloxazines other than riboflavin, alloxazines, dyes such asphthalocyanines, phenothiazine dyes (e.g. methylene blue, azure B, azureC, thionine, toluidine blue), porphyrin derivatives (e.g.dihematoporphyrin ether, hematoporphyrin derivatives, benzoporphyrinderivatives, alkyl-substituted sapphyrin), and merocyanine 540 (Prodouzet al., Blood Cells 1992, 18(1):101-14; Sofer, Gail, BioPharm, August2002).

In some embodiments, the pathogen inactivation is carried out using anINTERCEPT® Blood System (Cerus), such as the INTERCEPT® Blood System forPlasma. The INTERCEPT® Blood System is well known in the art as a systemfor pathogen inactivation, with widespread adoption in European bloodcenters and FDA approval in the United States. For greater descriptionof the INTERCEPT® Blood System and pathogen inactivation methods andcompositions related thereto, see, e.g., U.S. Pat. Nos. 5,399,719,5,556,993, 5,578,736, 5,585,503, 5,593,823, 5,625,079, 5,654,443,5,712,085, 5,871,900, 5,972,593, 6,004,741, 6,004,742, 6,017,691,6,194,139, 6,218,100, 6,503,699, 6,544,727, 6,951,713, 7,037,642, and7,611,831; and PCT publication numbers WO 1995000141, WO 1996014739, WO1997021346, WO 1998030327, WO 1999034914, and WO1999034915, thedisclosures of each of which are hereby incorporated by reference asthey relate to pathogen inactivation in blood products.

As described above, plasma or cryoprecipitate or cryo-poor plasma may besubjected to pathogen inactivation. An exemplary process for using theINTERCEPT® Blood System to pathogen inactivate plasma is as follows. Asample of plasma (e.g., containing one or more than one plasma units,AABB units) in the illumination container may be brought into contactwith amotosalen from the amotosalen container (e.g., by connectingthrough tubing and breaking the amotosalen container cannula to releasethe amotosalen). After sealing the illumination container, it may beilluminated with UV according to manufacturer's protocols. Onceilluminated, the plasma may be transferred through tubing into one ormore storage containers through a compound adsorption device (CAD).Optionally, if more than one storage container of plasma is to bepooled, they may be pooled into a larger blood bag (e.g., a 600-650 mLbag for three plasma units, e.g., 200 mL units, AABB plasma units; suchas a 600 mL PVC transfer pack). Cryoprecipitate may then be prepared(e.g., in the larger blood bag) as described herein. Liquid plasma maythen be removed, e.g., by draining into one or more bags. Optionally,more than one cryoprecipitate sample may be produced; if so, theindividual cryoprecipitates samples may be combined in a singlecontainer through use of a sterile dock/tubing. Cryoprecipitate may thenbe frozen and stored. It will be understood by one of skill in the artthat alternative steps, combinations of steps, and order of steps may befollowed.

In some embodiments, plasma or cryoprecipitate or cryo-poor plasma maybe pathogen-inactivated in a container (e.g., a blood bag or othercontainer described herein) suitable for photochemical inactivation ofplasma under sterile conditions. This container may be coupled to a CAD(e.g., as described and/or referenced above) such that plasma can betransferred from the container to the CAD under sterile conditions. Insome embodiments, the CAD may further be coupled to one or more secondcontainers, such that the plasma can be transferred from the CAD to theone or more second containers under sterile conditions. For example, one600 mL PVC transfer pack or other larger blood bag may be used for asingle second container, or more than one (e.g., three) smaller bloodbags (e.g., sized for one AABB unit) may be used as second containers.The one or more second containers may be suitable for freezingpathogen-inactivated plasma followed by thawing the pathogen-inactivatedplasma under conditions that provide for the formation ofcryoprecipitate. In some embodiments, a third container may be coupledto the one or more second containers, such that the pathogen-inactivatedplasma can be transferred from the CAD to the one or more secondcontainers to the third container under sterile conditions. The thirdcontainer may be suitable for freezing pathogen-inactivated plasmafollowed by thawing the pathogen-inactivated plasma under conditionsthat provide for the formation of cryoprecipitate. For example,pathogen-inactivated plasma from multiple (e.g., three) secondcontainers may be transferred to and combined within a larger thirdcontainer (e.g., a 600-650 mL bag) for subsequent cryoprecipitatepreparation.

Other pathogen inactivation systems include, for example, thosedescribed in PCT publication numbers WO 2012071135; WO 2012018484; WO2003090794; WO 2003049784; WO 1998018908; WO 1998030327; WO 1996008965;WO 1996039815; WO 1996039820; WO 1996040857; WO 1993000005; US patentapplication number US 20050202395; and U.S. Pat. Nos. 8,296,071 and6,548,242, the disclosures of which are hereby incorporated by referenceas they relate to pathogen inactivation in blood products. Whereaddition of a compound to the blood product is used for pathogeninactivation, whether the method requires illumination or not, in someinstances it is desirable to remove any residual pathogen inactivationcompound or by-product thereof.

Some pathogen inactivation methods may require the use of a removaldevice, i.e. a device for reducing the concentration of pathogeninactivation compound, such as a small organic compound, and by-productsthereof, in a unit of cryoprecipitate or plasma while substantiallymaintaining a desired biological activity of the cryoprecipitate orplasma. In some instances, the removal device comprises porous adsorbentparticles in an amount sufficient to reduce the pathogen inactivationcompound to below a desired concentration, wherein the adsorbentparticles have an affinity for the pathogen inactivation compound, whereit is understood that such adsorbent particle can be selected to bestadsorb the compound or compounds to be removed, with minimal effect oncomponents that should not be removed or damaged by contact with theadsorbent particle. A variety of adsorbent particles are known,including generally particles made from any natural or syntheticmaterial capable of interacting with compounds to be removed, includingparticulates made of natural materials such as activated carbon, silica,diatomaceous earth, and cellulose, and synthetic materials such ashydrophobic resins, hydrophilic resins or ion exchange resins. Suchsynthetic resins include, for example, carbonaceous materials,polystyrene, polyacrylic, polyacrylic ester, cation exchange resin, andpolystyrene-divinylbenzene. Detailed description of such removal devicessuitable for use in the methods as described herein can be found in PCTpublication numbers WO 1996040857, WO 1998030327, WO 1999034914, and WO2003078023, the disclosures of which are hereby incorporated byreference with respect to the discussion of such removal devices and theadsorbent particles and other materials used to prepare such devices.Exemplary adsorbent particles include, but are not limited to, Amberlite(Rohm and Haas) XAD-2, XAD-4, XAD-7, XAD-16, XAD-18, XAD-1180, XAD-1600,XAD-2000, XAD-2010; Amberchrom (Toso Haas) CG-71m, CG-71c, CG-161m,CG161c; Diaion Sepabeads (Mitsubishi Chemicals) HP20, SP206, SP207,SP850, HP2MG, HP20SS, SP20MS; Dowex (Dow Chemical) XUS-40285, XUS-40323,XUS-43493 (also referred to as Optipore V493 (dry form) or Optipore L493(hydrated form)), Optipore V503, Optipore SD-2; Hypersol Macronet(Purolite) MN-100, MN-102, MN-150, MN-152, MN-170, MN-200, MN-202,MN-250, MN-252, MN-270, MN-300, MN-400, MN-500, MN-502, Purosorb(Purolite) PAD 350, PAD 400, PAD 428, PAD 500, PAD 550, PAD 600, PAD700, PAD 900, and PAD 950. The material used to form the immobilizedmatrix comprises a low melting polymer, such as nylon, polyester,polyethylene, polyamide, polyolefin, polyvinyl alcohol, ethylene vinylacetate, or polysulfone. In one example, the adsorbent particlesimmobilized in a matrix are in the form of a sintered medium. While itis understood that the methods and devices described herein encompassremoval devices as are known in the art, such methods and devices may beexemplified using the removal device of an amotosalen inactivated bloodproduct as is commercially available. Some such removal devices containHypersol Macronet MN-200 adsorbent contained within a sintered matrix,where the sintered matrix comprises PL2410 plastic as a binder. In oneinstance, the removal device comprises Hypersol Macronet MN-200adsorbent in a sintered matrix comprising PL2410, wherein the HypersolMacronet MN-200 is in an amount of about 5 g dry weight equivalent.

As various resins may require different processing when used to make theremoval devices useful in the methods and devices as described herein,comparison of amounts of adsorbent resins described herein, unlessotherwise indicated, are comparison of the dry weight of the resin. Forexample, the resins are dried to <5% water prior to processing, and theequivalent of the dry weight of adsorbent is used in comparing amountsof resin in use. For example, Hypersol Macronet MN-200 is processed tostabilize the adsorbent, or what is typically referred to as wetting theadsorbent, so as to be directly usable upon contact with a blood productunit. Such a wetted sample may include, for example, about 50% glycerolor other suitable wetting agent. In some embodiments, the adsorbentresin is a polystyrene-divinylbenzene resin. In some embodiments, thepolystyrene-divinylbenzene resin is Hypersol Macronet MN-200. In someembodiments, the adsorbent is contained within a sintered matrix,wherein the sintered matrix comprises PL2410 binder. In someembodiments, Hypersol Macronet MN-200 adsorbent is contained within asintered matrix to provide a removal device.

Cryosupernatant Preparation

It will be appreciated by one of skill in the art that, in the processof generating a cryoprecipitate or cryoprecipitate composition, acryosupernatant (e.g., cryo-poor plasma, cryo-reduced plasma) of thepresent disclosure is also produced or formed. Such cryosupernatant mayhave medical uses of interest, such as infusion into a patient.

As such, disclosed herein are methods of preparing a cryo-poor plasma(e.g., pooled cryo-poor plasma, pooled cryosupernatant) for infusioninto a subject. In some embodiments, the methods comprise combining atleast a first plasma and a second plasma, and subjecting the combined(e.g., pooled) plasma to a pathogen inactivation process and freezing.In some embodiments, the at least first and second plasmas have acombined volume of at least about 550 mL and less than about 650 mL. Insome embodiments, the methods comprise freezing at least a firstpathogen-inactivated plasma and a second pathogen-inactivated plasma. Insome embodiments, the first and the second pathogen-inactivated plasmashave a combined volume of at least about 550 mL and less than about 650mL. In some embodiments, the first and the second pathogen-inactivatedplasmas each have a volume of at least about 550 mL and less than about650 mL. In some embodiments, the first and the secondpathogen-inactivated plasmas have a combined volume of about 600 mL. Insome embodiments, the first and the second pathogen-inactivated plasmaseach have a volume of about 600 mL. In some embodiments, three units(e.g., AABB plasma units) may be used.

In some embodiments, the first and the second pathogen-inactivatedplasmas may then be thawed under conditions that provide for theformation of cryoprecipitates (e.g., as described herein). In someembodiments, each cryoprecipitate may then be separated from thecorresponding cryosupernatant. In some embodiments, the twocryosupernatants may then be combined to form a pooled cryosupernatant.

In some embodiments, two pooled cryosupernatants (prepared, e.g., asdescribed above) may be combined. For example, two pooledcryosupernatants may be combined, where each of the pooledcryosupernatants is obtained from pooling cryosupernatants obtained frompathogen-inactivated plasmas totaling at least about 550 mL and lessthan about 650 mL, e.g., as described above. As such, in someembodiments, a pooled cryosupernatant may be obtained from 1100-1300 mLof pathogen-inactivated plasma.

In some embodiments, plasma or cryoprecipitate or cryo-poor plasma maybe pathogen-inactivated in a container (e.g., a blood bag or othercontainer described herein) suitable for photochemical inactivation ofplasma under sterile conditions. This container may be coupled to a CAD(e.g., as described and/or referenced above) such that plasma can betransferred from the container to the CAD under sterile conditions. Insome embodiments, this container may be coupled to an additional (e.g.,upstream) container suitable for mixing the one or more units of plasmawith a pathogen-inactivating compound (e.g., as described and/orreferenced herein). In some embodiments, the additional container iscoupled to the first container such that the one or more units of plasmain admixture with the pathogen-inactivating compound can be transferredfrom the additional container to the first container under sterileconditions. In some embodiments, the CAD may further be coupled to oneor more second containers, such that the plasma can be transferred fromthe CAD to the one or more second containers under sterile conditions.For example, one 600 mL PVC transfer pack or other larger blood bag maybe used for a single second container, or more than one (e.g., three)smaller blood bags (e.g., sized for one AABB unit) may be used as secondcontainers. The one or more second containers may be suitable forfreezing pathogen-inactivated plasma followed by thawing thepathogen-inactivated plasma under conditions that provide for theformation of cryoprecipitate. In some embodiments, a third container maybe coupled to the one or more second containers, such that thepathogen-inactivated plasma can be transferred from the CAD to the oneor more second containers to the third container under sterileconditions. The third container may be suitable for freezingpathogen-inactivated plasma followed by thawing the pathogen-inactivatedplasma under conditions that provide for the formation ofcryoprecipitate. For example, pathogen-inactivated plasma from multiple(e.g., three) second containers may be transferred to and combinedwithin a larger third container (e.g., a 600-650 mL bag) for subsequentcryoprecipitate preparation. In some embodiments, pathogen-inactivatedcryo-poor plasma can be transferred from the third container to a firstof the two or more second containers, and the precipitate can betransferred from the third container to a second of the two or moresecond containers. In some embodiments (e.g., when three or more secondcontainers are used), the pathogen-inactivated cryo-poor plasma istransferred from the third container to each of two second containersand the precipitate is transferred from the third container to a thirdsecond container. In some embodiments, the precipitate (e.g., theprecipitate in the third second container) is resuspended in about 80 mLto about 120 mL of pathogen-inactivated plasma (e.g., in about 100 mL ofpathogen-inactivated plasma), where the pathogen-inactivated plasma usedfor resuspension is optionally pathogen-inactivated cryo-poor plasmafrom the third container.

In some embodiments, cryosupernatant may be separated fromcryoprecipitate in one or more fourth containers (e.g., one or more600-650 mL bags). In some embodiments, the one or more fourth containersmay be configured to be coupled to one or more second containers or athird container, as described above, such that the supernatant can betransferred from the one or more second containers or the thirdcontainer to the one or more fourth containers under sterile conditionsto afford a pathogen-inactivated cryosupernatant contained within theone or more fourth containers and a pathogen-inactivated cryoprecipitatecontained within the one or more second containers or the thirdcontainer.

In some embodiments, a therapeutically effective amount ofpathogen-inactivated cryo-poor plasma is administered to a subject. Insome embodiments, the subject is suffering from one or more of burns,blunt trauma, penetrating trauma, and hemorrhage. In some embodiments,the administration results in fluid resuscitation of the subject.

In some embodiments, prior to administering the pathogen-inactivatedcryo-poor plasma to a subject, the pathogen-inactivated cryo-poor plasmais frozen (e.g., for frozen storage) and thawed (e.g., from frozenstorage). In some embodiments, the pathogen-inactivated cryo-poor plasmais administered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or7 days after thawing.

Further disclosed herein are methods for infusing a pathogen-inactivatedplasma composition (e.g., frozen plasma, fresh frozen plasma, PF24,apheresis plasma, cryo-poor plasma, cryosupernatant) of the presentdisclosure into a subject.

Use of Plasma Compositions

Pathogen-inactivated plasma compositions of the present disclosure maybe used for treating a variety of diseases and conditions. Thepathogen-inactivated plasma compositions may include for example apathogen-inactivated frozen plasma (e.g., whole blood collected plasma),such as a fresh frozen plasma (e.g., FFP) or a plasma frozen within 24hr (e.g., PF24), a pathogen-inactivated apheresis collected plasma,and/or a plasma supernatant from a cryoprecipitate process (e.g.,cryosupernatant, cryo-poor plasma). For example, pathogen-inactivatedplasma compositions of the present disclosure may be used for treating adisease or condition indicated for treatment by plasma exchange (e.g.,therapeutic plasma exchange) in a subject in need thereof, for exampleby administering to the subject a therapeutically effective amount ofthe pathogen-inactivated plasma composition by plasma exchange. Incertain embodiments, the disease or condition is indicated for treatmentwith albumin by plasma exchange. Pathogen-inactivated plasmacompositions of the present disclosure may also be used for treating adisease or condition indicated for treatment by intravenous infusionwith immunoglobulin (e.g., intravenous immunoglobulin infusion, IVIG) ina subject in need thereof, for example by administering to the subject atherapeutically effective amount of the pathogen-inactivated plasmacomposition by plasma exchange. In certain embodiments,pathogen-inactivated plasma compositions of the present disclosure maybe used for treating a disease or condition that is contra-indicated fortreatment with a plasma (e.g., frozen plasma, FFP, cryo-poor plasma),for example by administering a therapeutically effective amount of thepathogen-inactivated plasma composition to a subject suffering from thedisease or condition by plasma exchange. In some embodiments, apathogen-inactivated plasma composition of the present disclosure isadministered to a subject within 1 day, 2 days, 3 days, 4 days, 5 days,6 days, or 7 days after thawing (e.g., from frozen storage).

Pathogen-inactivated plasma compositions of the present disclosure alsomay be used for treating a neurologic disease or condition. Non-limitingexamples of neurologic diseases or conditions include, for example,Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy (CIDP), myasthenia gravis, paraproteinemic polyneuropathy(e.g., polyneuropathy associated with paraproteinaemias, paraproteinemicdemyelinating neuropathy), PANDAS, Lambert-Eaton myasthenic syndrome,acute exacerbation of multiple sclerosis, chronic focal encephalitisand/or neuromyelitis optica.

Pathogen-inactivated plasma compositions of the present disclosure alsomay be used for treating a hematologic disease or condition.Non-limiting examples of hematologic diseases or conditions include, forexample, hyperviscosity syndromes (e.g., paraproteinaemias,hyperviscosity in monoclonal gamopathies), cryoglobulinaemia (e.g.,severe/symptomatic), haemopoietic stem cell transplantation (e.g.,ABO-incompatible haemopoietic stem cell transplantation), pure red cellaplasia, cold agglutinin disease (e.g., life-threatening cold agglutinindisease), myeloma with cast nephropathy, red cell alloimmunisation inpregnancy, alloimmune thrombocytopenia and/or hemolytic disease of thenewborn. Other non-limiting examples of hematologic diseases orconditions include, for example, thrombotic thrombocytopenic purpura(TTP) and hemolytic uremic syndrome (e.g., HUS, atypical hemolyticuremic syndrome, autoantibody to factor H).

Pathogen-inactivated plasma compositions of the present disclosure alsomay be used for treating a renal disease or condition. Non-limitingexamples of renal diseases or conditions include, for example,Goodpasture's syndrome, antineutrophil cytoplasmic antibody(ANCA)-associated rapidly progressive glomerulonephritis, recurrentfocal segmental glomerular sclerosis and/or antibody-mediated renaltransplant rejection.

Pathogen-inactivated plasma compositions of the present disclosure alsomay be used for treating a metabolic disease or condition. Non-limitingexamples of metabolic diseases or conditions include, for example,familial hypercholesterolaemia (e.g., homozygous), Wilson's disease(e.g., fulminant) and/or Refsum's disease.

Pathogen-inactivated plasma compositions of the present disclosure alsomay be used for treating an immunologic disease or condition.Non-limiting examples of immunologic diseases or conditions include, forexample, catastrophic antiphospholipid syndrome and/or cerebral systemiclupus erythematosus (SLE).

Pathogen-inactivated plasma compositions of the present disclosure maybe used for treating one or more of the following diseases orconditions, whereby a therapeutically effective amount of thepathogen-inactivated plasma composition is administered to a subject inneed thereof by plasma exchange (e.g., therapeutic plasma exchange):Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy (e.g., CIDP, chronic inflammatory demyelinatingpolyradiculoneuropathy), myasthenia gravis, paraproteinemicpolyneuropathy (e.g., polyneuropathy associated with paraproteinaemias,paraproteinemic demyelinating neuropathy), polyneuropathy associatedwith monoclonal gammopathy of undetermined significance (MGUS), PANDAS(Pediatric Autoimmune Neuropsychiatric Disorders Associated withStreptococcal Infections), hyperviscosity syndromes (e.g.,paraproteinaemias, hyperviscosity in monoclonal gamopathies),cryoglobulinaemia (e.g., severe, symptomatic), Goodpasture's syndrome,antineutrophil cytoplasmic antibody (ANCA)-associated rapidlyprogressive glomerulonephritis, recurrent focal segmental glomerularsclerosis, antibody-mediated renal transplant rejection, familialhypercholesterolaemia (e.g., homozygous), Wilson's disease (e.g.,fulminant Wilson's disease), Lambert-Eaton myasthenic syndrome, acuteexacerbation of multiple sclerosis, chronic focal encephalitis,neuromyelitis optica, haemopoietic stem cell transplantation (e.g.,ABO-incompatible haemopoietic stem cell transplantation), pure red cellaplasia, cold agglutinin disease (e.g., life-threatening cold agglutinindisease), hemolytic uremic syndrome (e.g., HUS, atypical hemolyticuremic syndrome, autoantibody to factor H), thrombotic thrombocytopenicpurpura (TTP), myeloma with cast nephropathy, red cell alloimmunisationin pregnancy, catastrophic antiphospholipid syndrome, systemic lupuserythematosus (e.g., cerebral systemic lupus erythematosus, SLE),Refsum's disease, alloimmune thrombocytopenia, hemolytic disease of thenewborn, Kawasaki disease, toxic epidermal necrolysis, Stevens Johnsonsyndrome (SJS), autoimmune haemolytic anaemia, clotting (e.g.,coagulation) factor inhibitors, haemophagocytic syndrome,post-transfusion purpura, chronic inflammatory demyelinatingpolyradiculoneuropathy, inflammatory myelopathies, multifocal motorneuropathy, Rasmussen syndrome (e.g., Rasmussen encephalitis), stiffperson syndrome, autoimmune congenital heart block, autoimmune uveitis,immunobullous diseases, necrotising staphylococcal sepsis, Clostridiumdifficile colitis (e.g., severe, recurrent), staphylococcal orstreptococcal toxic shock syndrome, immune-mediated solid organtransplant rejection (e.g., treating or preventing antibody-mediatedrejection after solid organ transplantation, treating or preventingABO-incompatible solid organ transplant rejection, treating orpreventing HLA-incompatible solid organ transplant rejection,desensitization to solid organ transplant), Wegener's granulomatosis,cryoglobulinemia, focal segmental glomerulosclerosis (e.g., recurrent),thrombotic microangiopathy (TMA) (e.g., drug-associated TMA), B-cellchronic lymphocytic leukemia (CLL), multifocal motor neuropathy (MMN),asthma, treatment or prevention of acute graft versus host disease(GVHD) and/or infection after allogeneic bone marrow transplant (BMT),myositis (e.g., dermatomyositis, polymyositis), CMV induced pneumonitisin solid organ transplantation (SOT), rheumatoid arthritis,Lambert-Eaton myasthenic syndrome (LEMS), Still's disease, vasculitides,bacterial infection in pediatric HIV (e.g., prevention), inclusion bodymyositis (IBM), acute disseminated encephalomyelitis, cardiomyopathy(e.g., dilated cardiomyopathy, idiopathic dilated cardiomyopathy),Henoch-Schonlein purpura (e.g., HSP, anaphylactoid purpura, purpurarheumatica), hyperleukocytosis, nephrogenic systemic fibrosis,paraneoplastic neurological syndromes, Sydenham's chorea, scleroderma,sudden sensorineural hearing loss, acute liver failure, aplastic anemia,burn shock resuscitation, cardiac transplant (e.g., treating orpreventing ABO-incompatible cardiac transplant rejection, treating orpreventing HLA-incompatible cardiac transplant rejection,desensitization to transplant), heparin-induced thrombocytopenia,hypertriglyceridemic pancreatitis, liver transplant (e.g., treating orpreventing ABO-incompatible liver transplant rejection, treating orpreventing HLA-incompatible liver transplant rejection, desensitizationto transplant), lung allograft rejection, pemphigus vulgaris, poisoning,overdose, envenomation, renal transplant (e.g., treating or preventingABO-incompatible renal transplant rejection, treating or preventingHLA-incompatible renal transplant rejection, desensitization totransplant), thyroid storm, sepsis (e.g., sepsis with multi-organfailure), immune complex rapidly progressive glomerulonephritis.

In certain embodiments, pathogen-inactivated plasma compositions of thepresent disclosure may be used for treating a disease or conditionselected from the group consisting of Guillain-Barré syndrome, chronicinflammatory demyelinating polyneuropathy (e.g., CIDP, chronicinflammatory demyelinating polyradiculoneuropathy), myasthenia gravis,paraproteinemic polyneuropathy (e.g., polyneuropathy associated withparaproteinaemias, paraproteinemic demyelinating neuropathy),polyneuropathy associated with monoclonal gammopathy of undeterminedsignificance (MGUS), PANDAS (Pediatric Autoimmune NeuropsychiatricDisorders Associated with Streptococcal Infections), hyperviscositysyndromes (e.g., paraproteinaemias, hyperviscosity in monoclonalgamopathies), cryoglobulinaemia (e.g., severe, symptomatic),Goodpasture's syndrome, antineutrophil cytoplasmic antibody(ANCA)-associated rapidly progressive glomerulonephritis, recurrentfocal segmental glomerular sclerosis, antibody-mediated renal transplantrejection, familial hypercholesterolaemia (e.g., homozygous), Wilson'sdisease (e.g., fulminant Wilson's disease), Lambert-Eaton myasthenicsyndrome, acute exacerbation of multiple sclerosis, chronic focalencephalitis, neuromyelitis optica, haemopoietic stem celltransplantation (e.g., ABO-incompatible haemopoietic stem celltransplantation), pure red cell aplasia, cold agglutinin disease (e.g.,life-threatening cold agglutinin disease), myeloma with castnephropathy, red cell alloimmunisation in pregnancy, catastrophicantiphospholipid syndrome, systemic lupus erythematosus (e.g., cerebralsystemic lupus erythematosus, SLE), Refsum's disease, alloimmunethrombocytopenia, hemolytic disease of the newborn, Kawasaki disease,toxic epidermal necrolysis, Stevens Johnson syndrome (SJS), autoimmunehaemolytic anaemia, clotting (e.g., coagulation) factor inhibitors,haemophagocytic syndrome, post-transfusion purpura, chronic inflammatorydemyelinating polyradiculoneuropathy, inflammatory myelopathies,multifocal motor neuropathy, Rasmussen syndrome (e.g., Rasmussenencephalitis), stiff person syndrome, autoimmune congenital heart block,autoimmune uveitis, immunobullous diseases, necrotising staphylococcalsepsis, Clostridium difficile colitis (e.g., severe, recurrent),staphylococcal or streptococcal toxic shock syndrome, immune-mediatedsolid organ transplant rejection (e.g., treating or preventingantibody-mediated rejection after solid organ transplantation, treatingor preventing ABO-incompatible solid organ transplant rejection,treating or preventing HLA-incompatible solid organ transplantrejection, desensitization to solid organ transplant), Wegener'sgranulomatosis, cryoglobulinemia, focal segmental glomerulosclerosis(e.g., recurrent), thrombotic microangiopathy (TMA) (e.g.,drug-associated TMA), B-cell chronic lymphocytic leukemia (CLL),multifocal motor neuropathy (MMN), asthma, treatment or prevention ofacute graft versus host disease (GVHD) and/or infection after allogeneicbone marrow transplant (BMT), myositis (e.g., dermatomyositis,polymyositis), CMV induced pneumonitis in solid organ transplantation(SOT), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome (LEMS),Still's disease, vasculitides, bacterial infection in pediatric HIV(e.g., prevention), inclusion body myositis (IBM), acute disseminatedencephalomyelitis, cardiomyopathy (e.g., dilated cardiomyopathy,idiopathic dilated cardiomyopathy), Henoch-Schonlein purpura (e.g., HSP,anaphylactoid purpura, purpura rheumatica), hyperleukocytosis,nephrogenic systemic fibrosis, paraneoplastic neurological syndromes,Sydenham's chorea, scleroderma, sudden sensorineural hearing loss, acuteliver failure, aplastic anemia, burn shock resuscitation, cardiactransplant (e.g., treating or preventing ABO-incompatible cardiactransplant rejection, treating or preventing HLA-incompatible cardiactransplant rejection, desensitization to transplant), heparin-inducedthrombocytopenia, hypertriglyceridemic pancreatitis, liver transplant(e.g., treating or preventing ABO-incompatible liver transplantrejection, treating or preventing HLA-incompatible liver transplantrejection, desensitization to transplant), lung allograft rejection,pemphigus vulgaris, poisoning, overdose, envenomation, renal transplant(e.g., treating or preventing ABO-incompatible renal transplantrejection, treating or preventing HLA-incompatible renal transplantrejection, desensitization to transplant), thyroid storm, sepsis (e.g.,sepsis with multi-organ failure), immune complex rapidly progressiveglomerulonephritis.

In certain embodiments, pathogen-inactivated plasma compositions of thepresent disclosure may be used for treating hemolytic uremic syndrome(e.g., HUS, atypical hemolytic uremic syndrome, autoantibody to factorH) or thrombotic thrombocytopenic purpura (TTP). For example, in someembodiments, the disclosure provides a method of treatingthrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of pathogen-inactivated plasmacomposition. In some embodiments, the pathogen-inactivated plasmacomposition comprises pathogen-inactivated cryo-poor plasma. In someembodiments, the pathogen-inactivated plasma composition is administeredby plasma exchange.

Treatment with a pathogen-inactivated plasma composition of the presentdisclosure may be accomplished by administering a therapeuticallyeffective amount of the pathogen-inactivated plasma by plasma exchange(e.g., therapeutic plasma exchange) to a subject in need thereof. Incertain embodiments, a pathogen-inactivated plasma composition of thepresent disclosure may be administered in conjunction with (e.g.,concurrently with, consecutively with, after) the administration ofimmunoglobulin by intravenous infusion (e.g., intravenous immunoglobulininfusion, IVIG).

Therapeutic plasma exchange is a treatment process well known in theart, whereby blood is separated into plasma and cellular components,followed by mixing of the cellular components with a replacement fluidand reinfusion into the patient (Winters, 2012, Hematology ASH EducationBook 2012:7-12). TPE is generally an automated process performed usingcommercially available apheresis (e.g., plasmapheresis) devices, whichcan be divided into two broad categories: those that use filters toseparate the plasma from the cellular components based on size, andthose that use centrifugation to separate components based on density.

A plasma exchange using a plasma composition of the present disclosuremay be performed using a variety of pathogen-inactivated plasmacomposition volumes, such as for example volumes of the plasmacomposition greater than to about equal to (e.g., 1-2 times, 1-1.5times) or less than to about equal to (e.g., 0.5-1 times) the subject'splasma volume. For example, in certain embodiments plasma exchange maybe achieved with a volume of the plasma composition similar to thesubject's plasma volume. Alternatively or in addition, plasma exchangemay be achieved with a volume of the plasma composition more than thesubject's plasma volume. For example, plasma exchange may be achievedwith a volume of the plasma composition about 1 times, about 1.1 times,about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times,about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, orabout 2 times the subject's plasma volume. Alternatively or in addition,plasma exchange may be achieved with a volume of the plasma compositionless than the subject's plasma volume. For example, plasma exchange maybe achieved with a volume of the plasma composition about 0.9 times,about 0.8 times, about 0.7 times, about 0.6 times or about 0.5 timesless than the subject's plasma volume. Plasma exchange volumes may alsobe indicated as volume per patient weight. For example, plasma exchangemay be achieved with a volume of the plasma composition comprising about20 mL/kg, about 25 mL/kg, about 30 mL/kg, about 35 mL/kg, about 40mL/kg, about 45 mL/kg, about 50 mL/kg, about 55 mL/kg, about 60 mL/kg,about 65 mL/kg, about 70 mL/kg, about 75 mL/kg or about 80 mL/kg patientbody weight.

A plasma exchange of the present disclosure may be performed one time ormore than one time, for example, the plasma exchange may be performed atleast two times, at least three times, at least four times or at leastfive times or more. In certain embodiments, the plasma exchange isperformed 2-5 times. When multiple plasma exchanges (e.g., 2-5 plasmaexchanges) are used, the multiple plasma exchanges may be performedwithin a defined period of time. For example, a plasma exchange may beperformed 2-5 times within a period of 4 weeks, within a period or threeweeks, within a period of two weeks or within a period of one week. Incertain embodiments, five plasma exchanges are performed within a periodof 4 weeks, within a period or three weeks, within a period of two weeksor within a period of one week. In certain embodiments, four plasmaexchanges are performed within a period of 4 weeks, within a period orthree weeks, within a period of two weeks or within a period of oneweek. In certain embodiments, three plasma exchanges are performedwithin a period of 4 weeks, within a period or three weeks, within aperiod of two weeks or within a period of one week. In certainembodiments, two plasma exchanges are performed within a period of 4weeks, within a period or three weeks, within a period of two weeks orwithin a period of one week.

Certain aspects of the present disclosure relate to methods of treatinga subject suffering from a trauma. In some embodiments, the methodsinclude administering to the subject a therapeutically effective amountof a pathogen-inactivated plasma composition of the present disclosure.For example, in some embodiments, the subject is suffering from burns(including without limitation major burns, e.g., ≥20% of total bodysurface area), blunt trauma, or penetrating trauma. In some embodiments,the subject is suffering from hemorrhage, e.g., internal hemorrhage.

Certain aspects of the present disclosure relate to methods of treatinga subject suffering from burns. In some embodiments, the methods includeadministering to the subject a therapeutically effective amount of apathogen-inactivated plasma composition of the present disclosure. Forexample, in some embodiments, the burns include major burns, e.g., ≥20%of total body surface area.

In some embodiments, the methods include fluid resuscitation. In someembodiments, the methods reduce hemorrhage, hemorrhagic shock, and/orendothelial permeability in the subject. In some embodiments, themethods reduce or prevent traumatic coagulopathy in the subject. In someembodiments, treatment with a method of the present disclosure resultsin decreased subject mortality (e.g., increased survival rate).

Certain aspects of the present disclosure relate to methods ofresuscitation from hemorrhagic shock in a subject suffering from atrauma, e.g., hemorrhagic shock. In some embodiments, the methodsinclude administering to the subject a therapeutically effective amountof a pathogen-inactivated plasma composition of the present disclosure.In some embodiments, the subject is suffering from internal hemorrhage.

Certain aspects of the present disclosure relate to methods ofresuscitation suffering from burns. In some embodiments, the methodsinclude administering to the subject a therapeutically effective amountof a pathogen-inactivated plasma composition of the present disclosure.For example, in some embodiments, the burns include major burns, e.g.,≥20% of total body surface area.

In some embodiments, the methods reduce hemorrhage and/or endothelialpermeability in the subject. In some embodiments, the methods reduce orprevent trauma-induced endotheliopathy and/or traumatic coagulopathy inthe subject. In some embodiments, treatment with a method of the presentdisclosure results in decreased subject mortality (e.g., increasedsurvival rate).

In some embodiments, a therapeutically effective amount of apathogen-inactivated plasma composition comprising pathogen-inactivatedfrozen plasma is administered to a subject. In some embodiments, thepathogen-inactivated plasma composition comprises pathogen-inactivatedfresh frozen plasma. In some embodiments, the pathogen-inactivatedplasma composition comprises pathogen-inactivated cryo-poor plasma asdescribed herein.

In some embodiments, a pathogen-inactivated plasma composition of thepresent disclosure is administered after freezing, optional storage, andthawing. For example, in some embodiments, a pathogen-inactivated plasmacomposition of the present disclosure is administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days after thawing (e.g.,post-storage thawing as described herein). In other embodiments, thepathogen-inactivated plasma composition is a lyophilized or freeze-driedplasma composition. For example, in some embodiments, apathogen-inactivated plasma composition of the present disclosure isadministered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7days after reconstitution. In some embodiments, a pathogen-inactivatedplasma composition of the present disclosure is first administered lessthan 24 hours after the onset of trauma (e.g., an event which resultedin trauma).

Treatment of trauma in a subject using a pathogen-inactivated plasmacomposition of the present disclosure may be performed using a varietyof volumes. For example, in certain embodiments the volume of the plasmacomposition administered (e.g., infused) may comprise a volume requiredto achieve an increase in blood pressure (e.g., systolic blood pressure)to a desired level, such as for example, to at least 50 mmHg, at least55 mmHg, at least 60 mmHg, at least 65 mmHg, at least 70 mmHg, at least75 mmHg, at least 80 mmHg, at least 85 mmHg, at least 90 mmHg, at least95 mmHg, or at least 100 mmHg. In certain embodiments, additionalvolumes of the plasma composition may be administered to maintain theblood pressure at a desired level, such as any of the aforementionedlevels. Alternatively or in addition, the volume of plasma compositionadministered may comprise the volume required to achieve and/or maintaina palpable pulse (e.g., radial pulse), for example a palpable pulse of adesired strength (e.g., such that it is no longer faint or weak) asdetermined by medical personnel. In some embodiments, administration ofthe plasma composition is in conjunction with one or more othermedically accepted bleeding control procedures.

Alternatively or in addition, in subjects suffering from burns, such asfor example, major burns (e.g., burns≥20% of total body surface area,TBSA), the volume of a pathogen-inactivated plasma compositionadministered may be calculated prior to administration, for example,based on the subject's weight and the % TBSA of the burns. For example,the volume of plasma administered may be in a range of about 1-5 mL perkg subject body weight per % burn TBSA (mL/kg/% burn), about 2-5 mL/kg/%burn, about 2-4 mL/kg/% burn, about 2-3 mL/kg/% burn, or about 3-4mL/kg/% burn, or about 1 mL/kg/% burn, about 2 mL/kg/% burn, about 3mL/kg/% burn, about 4 mL/kg/% burn, or about 5 mL/kg/% burn.

Alternatively or in addition, the volume of a pathogen-inactivatedplasma composition of the present disclosure may be titrated as anamount to maintain renal perfusion to obtain a target urinary output,such as for example about 0.5 ml/kg/hr for adults or about 1 ml/kg/hrfor young pediatric patients.

Administration of a pathogen-inactivated plasma composition of thepresent disclosure may be about 1 hour, about 2 hours, about 3 hours,about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 10hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours,about 36 hours, about 48 hours, about 72 hours, about 96 hours or about120 hours after the onset of trauma (e.g., medical diagnosis of trauma,event which resulted in onset of trauma). Alternatively or in addition,administration of a pathogen-inactivated plasma composition may beinitiated within (e.g., less than) about 24 hours, within about 20hours, within about 16 hours, within about 12 hours, within about 10hours, within about 8 hours, within about 6 hours, within about 5 hours,within about 4 hours, within about 3 hours, within about 2 hours orwithin about 1 hours after the onset of trauma.

Administration of a desired volume of a pathogen-inactivated plasmacomposition of the present disclosure may be achieved by administeringmore than one unit of a pathogen-inactivated plasma composition. Forexample, at least two, at least three, at least four, at least 5 or moreunits many be administered to the subject. Administration of the desiredvolume occur over a desired time period, such as for example, over aperiod of about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 16hours, about 20 hours, or about 24 hours or more. In certainembodiments, administration of a desired volume may be divided betweentwo time periods, such as for example, half of the desired volume within8 hours of trauma onset and the other half within 24 hours of traumaonset.

In some embodiments, administration of a pathogen-inactivated plasmacomposition of the present disclosure is followed by administration ofat least one additional intravenous fluid. Suitable intravenous fluidsare known in the art and can include, without limitation, colloid suchas albumin or starch, or crystalloid such as Ringer's lactate orHartmann solution.

Processing Sets

Certain aspects of the present disclosure relate to processing sets. Theprocessing sets of the present disclosure may find use, inter alia, inpreparing a pathogen-inactivated cryoprecipitate, e.g., as describedherein.

In some embodiments, a processing set of the present disclosure includesa first container within which a psoralen of the present disclosure canbe photoactivated in the presence of one or more units of plasma understerile conditions (e.g., as described and/or referenced herein). Insome embodiments, the processing set further includes a compoundabsorption device (CAD) coupled to the first container such that the oneor more units of plasma can be transferred from the first container tothe compound absorption device under sterile conditions. In someembodiments, the processing set further includes one or more secondcontainers. In some embodiments, each of the one or more secondcontainers is coupled to the compound absorption device such that theone or more units of plasma can be transferred from the compoundabsorption device to the one or more second containers under sterileconditions, e.g., to provide pathogen-inactivated plasma suitable forinfusion into a subject. As non-limiting examples, the one or moresecond containers could include one 600 mL PVC transfer pack or otherlarger blood bag, or more than one (e.g., three) smaller blood bags(e.g., sized for one AABB unit). In some embodiments, the one or moresecond containers are suitable for freezing the pathogen-inactivatedplasma followed by thawing of the pathogen-inactivated plasma underconditions that provide for the formation of a precipitate and asupernatant.

In some embodiments, a processing set of the present disclosure furtherincludes a third container. In some embodiments, the third container isconfigured to be coupled to the one or more second containers such thatthe pathogen-inactivated plasma can be transferred from the one or moresecond containers to the third container under sterile conditions. Insome embodiments, the third container is suitable for freezing thepathogen-inactivated plasma followed by thawing of thepathogen-inactivated plasma under conditions that provide for theformation of a precipitate and a supernatant. In some embodiments, thethird container may be e.g., a 600-650 mL bag.

In some embodiments, a processing set of the present disclosure furtherincludes one or more fourth containers. In some embodiments, the one ormore fourth containers are configured to be coupled to the one or moresecond containers as described above or to the third container asdescribed above such that the supernatant can be transferred from theone or more second containers or the third container to the one or morefourth containers under sterile conditions, e.g., to afford apathogen-inactivated cryosupernatant of the present disclosure containedwithin the one or more fourth containers and a pathogen-inactivatedcryoprecipitate of the present disclosure contained within the one ormore second containers or the third container. In some embodiments, thefourth container is suitable for storage of a pathogen-inactivatedcryoprecipitate of the present disclosure under conditions in which thepathogen-inactivated cryoprecipitate is frozen. In some embodiments, twoor more fourth containers are used. The two or more fourth containersmay be configured to be coupled to one another while each of the two ormore fourth containers contains pathogen-inactivated cryoprecipitatesuch that the cryoprecipitate contained within the two or more fourthcontainers can be combined in one of the two or more fourth containers.In some embodiments, a fourth container may be e.g., a 600-650 mL bag.Non-limiting examples of processing sets of the present disclosure areas follows.

In some embodiments, a processing set includes a first container withinwhich a psoralen can be photoactivated in the presence of one or moreunits of plasma under sterile conditions; a compound absorption device(CAD) coupled to the first container such that the plasma can betransferred from the first container to the compound absorption deviceunder sterile conditions; one or more second containers, each of whichis coupled to the compound absorption device such that the plasma can betransferred from the compound absorption device to the one or moresecond containers under sterile conditions to providepathogen-inactivated plasma suitable for infusion into a subject; and athird container, which is configured to be coupled to the one or moresecond containers such that the pathogen-inactivated plasma can betransferred from the one or more second containers to the thirdcontainer under sterile conditions. In some embodiments, the one or moresecond containers are suitable for freezing the pathogen-inactivatedplasma followed by thawing of the pathogen-inactivated plasma underconditions that provide for the formation of a precipitate and asupernatant. In some embodiments, the third container is coupled to theone or more second containers such that the supernatant can betransferred from the one or more second containers to the thirdcontainer under sterile conditions to afford a pathogen-inactivatedcryosupernatant contained within the third container and apathogen-inactivated cryoprecipitate contained within the one or moresecond containers.

In other embodiments, a processing set includes a first container withinwhich a psoralen can be photoactivated in the presence of one or moreunits of plasma under sterile conditions; a compound absorption device(CAD) coupled to the first container such that the plasma can betransferred from the first container to the compound absorption deviceunder sterile conditions; one or more second containers, each of whichis coupled to the compound absorption device such that the plasma can betransferred from the compound absorption device to the one or moresecond containers under sterile conditions to providepathogen-inactivated plasma suitable for infusion into a subject; athird container, which is configured to be coupled to the one or moresecond containers such that the pathogen-inactivated plasma can betransferred from the one or more second containers to the thirdcontainer under sterile conditions; and one or more fourth containers,each of which is configured to be coupled to the third container suchthat the supernatant can be transferred from the third container to theone or more fourth containers under sterile conditions to afford apathogen-inactivated cryosupernatant contained within the one or morefourth containers and a pathogen-inactivated cryoprecipitate containedwithin the third container. In some embodiments, the third container issuitable for freezing the pathogen-inactivated plasma followed bythawing of the pathogen-inactivated plasma under conditions that providefor the formation of a precipitate and a supernatant.

Further non-limiting examples of processing sets are illustrated inFIGS. 1A-3B. Exemplary processing set 100 shown in FIG. 1A includesoptional plasma bag 102 containing the donor plasma to be pathogeninactivated, container 104 that contains a pathogen inactivationcompound (PIC, e.g., a psoralen), and bag 106 for photoactivation of theplasma (e.g., a first container of the present disclosure).Photoactivation bag 106 is coupled to CAD 108 through tubing 110, whichallows for the transfer of plasma after photoactivation to the CAD. CAD108 in turn is coupled to three smaller blood bags 112, 114, and 116(e.g., second containers of the present disclosure) through tubing 118,which allows the plasma to pass through the CAD (e.g., to remove freephotoproducts and/or unreacted pathogen inactivation compound) beforebeing collected in the smaller blood bags. Optional larger bag 122 forfreezing the plasma to form cryoprecipitate (e.g., a third container ofthe present disclosure) and optional larger bag 124 for separating thecryoprecipitate from the cryosupernatant (e.g., a fourth container ofthe present disclosure), which may be sterile docked (e.g., usingsterile connect 126) to the tubing between the CAD 108 and the three-waylead 120 of tubing 118 after collection of the PI plasma in the threebags, are also depicted.

An alternative configuration for processing set 100 is shown in FIG. 1B,where the cryoprecipitate is separated from the cryosupernatant byflowing the cryosupernatant from sterile-docked third container 122 backinto the three smaller bags 112, 114, and 116 (e.g., second containersof the present disclosure), rather than into the optional fourthcontainer 124.

In other embodiments, the cryoprecipitate is separated from thecryosupernatant by flowing the cryosupernatant from sterile-docked thirdcontainer 122 back into smaller bags 112 and 114. The cryoprecipitate in122 may then be resuspended in a small volume of cryo-poor plasmasupernatant (e.g., about 100 mL) and transferred to smaller bag 116,resulting in two smaller bags 112 and 114 containing cryo-poor plasma(CPP) and smaller bag 116 containing resuspended cryoprecipitate.

Another alternative configuration for processing set 100 is shown inFIG. 1C. This configuration includes optional container 128 that issterile connected or docked with third container 122 through sterileconnect 130. This configuration allows two cryosupernatant preparationsmade from pathogen-inactivated plasma (e.g., prepared in 122 and 128) tobe combined.

The exemplary processing set 200 shown in FIG. 2A, includes optionalplasma bag 202 containing the donor plasma to be pathogen inactivated,container 204 that contains a pathogen inactivation compound (PIC),photoactivation bag 206, and CAD 208 coupled to photoactivation bag 206with tubing 210 as described above, and additionally a pre-attached(e.g., integrated) third container 222. After collection of thepathogen-inactivated plasma in the three bags 212, 214, and 216, thethree units of PI plasma are pooled by transferring into larger bag 222(e.g., a third container of the present disclosure) for freezing to formcryoprecipitate and for separating cryoprecipitate from thecryosupernatant. As shown in FIG. 2B, cryosupernatant bag 224 (e.g., afourth container of the present disclosure) may be used to collect thecryosupernatant after freezing (this is depicted as an optionalcomponent in FIG. 2A). This cryosupernatant bag may be connected to thelarger freezing bag via tubing with common tubing clamp 226. Analternative configuration is shown in FIG. 2C, where the cryoprecipitateis separated from the cryosupernatant by flowing the cryosupernatantback into the three smaller bags 212, 214, and 216 (e.g., secondcontainers of the present disclosure) using tubing 228, rather than intothe fourth container 224 shown in FIG. 2B.

The exemplary processing set 300 shown in FIG. 3A includes optionalplasma bag 302 containing the donor plasma to be pathogen inactivated,container 304 that contains a pathogen inactivation compound (PIC),photoactivation bag 306, and CAD 308 coupled to photoactivation bag 306with tubing 310 as described above. However, in this example, a single,larger (e.g., 800 mL) bag 312 (e.g., a third container of the presentdisclosure) replaces the three smaller bags (e.g., 212, 214, and 216).This bag 312 may be used for pathogen-inactivated plasma collectionafter photoactivation, as well as freezing/thawing for production ofcryoprecipitate. The optional bag for cryosupernatant (e.g., 314) alsodepicted could be a pre-attached (e.g., integrated) part of the set withclamp 316 or alternatively sterile docked after PI plasma collection. InFIG. 3B, this cryosupernatant bag 314 (e.g., a fourth container of thepresent disclosure) is an integral part of set 300 coupled to thecryoprecipitate bag 312 (e.g., via tubing and a tubing clamp 316) andused to collect the cryosupernatant.

In any of the processing sets of the present disclosure, the firstcontainer (e.g., 106, 206, and/or 306) and the CAD (e.g., 108, 208,and/or 308) may be separated in a sterile manner from the rest of thecomponents, such as the PI plasma and cryoprecipitate containers (e.g.,112, 114, 116, 212, 214, 216, and/or 312), e.g., before freezing.

As described herein, in some embodiments, two or more cryoprecipitatepreparations of the present disclosure can be combined or pooled.Exemplary technique 400 for this pooling is shown in FIG. 4. Containers402 and 404 contain a first and a second cryoprecipitate preparation,respectively. They are combined in FIG. 4 by sterile docking, e.g.,using sterile connect 406. The technique illustrated in FIG. 4 may beapplied to any of the cryoprecipitate preparations described herein,e.g., the cryoprecipitate preparations made from pathogen-inactivatedplasma contained in containers 122, 222, and/or 312.

Exemplary processing set 500 is shown in FIG. 5. Integrated processingset 500 allows for the production and combining or pooling of two largercryoprecipitate preparations, e.g., as described herein. Processing set500 includes one or more optional plasma containers (e.g., as shown byoptional plasma container 502). Container(s) 502 is coupled to container504, which contains a pathogen inactivation compound (PIC).Pathogen-inactivated plasma is then split into first and secondphotoactivation bags 506 and 508 (respectively), which in turn arecoupled to first and second CADs 510 and 512 (respectively). CADs 510and 512 are then coupled to first and second bags 514 and 516(respectively), which are used for pathogen-inactivated plasmacollection after photoactivation, as well as freezing/thawing forproduction of cryoprecipitate. For example, in some embodiments, 514and/or 516 are larger (e.g., 800 mL) bags (e.g., third containers of thepresent disclosure), similar to bag 312 described above. Bag 514 isconnected (e.g., through tubing 518) to cryosupernatant bags 520, 522,and 524 (e.g., fourth containers of the present disclosure) forcollection of cryo-poor plasma. Similarly, bag 516 is connected (e.g.,through tubing 528) to cryosupernatant bags 530, 532, and 534 (e.g.,fourth containers of the present disclosure) for collection of cryo-poorplasma. In some embodiments, bags 514 and 516 are themselves connectedvia tubing 526, e.g., to allow the pathogen-inactivated cryoprecipitatepreparations contained therein to be combined or pooled.

Exemplary processing set 600 is shown in FIG. 6. Integrated processingset 600 represents another configuration that allows for the productionand combining or pooling of two larger cryoprecipitate preparations,e.g., as described herein. Processing set 600 includes one or moreoptional plasma containers (e.g., as shown by optional plasma container602). Container(s) 602 is coupled to container 604, which contains apathogen inactivation compound (PIC). Container 604 is then coupled tomixing container 606, which is used to contain the plasma/PIC mixture(optionally, as depicted in FIG. 6, container 602 may be coupleddirectly to mixing container 606 without 604 as an intermediary). Theplasma/PIC mixture is then split into first and second photoactivationbags 608 and 610 (respectively). After photoactivation, the splitplasma/PIC mixtures are then passed through CAD 612 and into bag 614,which is used for pathogen-inactivated plasma collection afterphotoactivation, as well as freezing/thawing for production ofcryoprecipitate. In some embodiments, bag 614 is a larger (e.g., 800 mL)bag (e.g., a third container of the present disclosure), similar to bag312 described above. One or more cryosupernatant bags (e.g., bags 616,618, 620, 622, 624, and 626) are connected to bag 614 for collection ofcryo-poor plasma.

It is to be understood that any of the processing sets of the presentdisclosure may be used in any of the methods of the present disclosure,or used to contain and/or process any of the plasma compositions,including for example the cryoprecipitates, cryoprecipitatecompositions, and/or cryo-poor plasmas (cryosupernatants) of the presentdisclosure.

The disclosure is illustrated further by the following examples, whichare not to be construed as limiting the disclosure in scope or spirit tothe specific procedures described in them.

EXAMPLES Example 1: Preparation of Pathogen Inactivated Cryoprecipitateand Cryo-Poor Plasma

Multiple blood group O negative units of liquid plasma units from theday of draw were pooled and split to obtain multiple plasma units forprocessing, each with a final volume 585 to 650 mL. Pathogeninactivation and preparation of cryoprecipitate and cryo-poor plasma wasundertaken with the pooled plasma units. The plasma was subjected tophotochemical pathogen inactivation using the commercially availableINTERCEPT Blood System for Plasma (Cerus Corporation). In the case offour of the pooled units subjected to INTERCEPT treatment, the pathogeninactivated plasma collected in the 3 storage bags of the INTERCEPTprocessing set (see e.g., 112, 114, and 116 in FIG. 1B) was transferredto a sterile-docked (sterile-connected), single 1000 mL transfer bag(see e.g., 122 in FIG. 1B) as large volume unit preparations. Two otherof the pooled units subjected to INTERCEPT treatment were maintained inthe 3 storage bags as smaller volume individual “single unit”preparations. The pathogen inactivated plasma units were then frozen at−30° C. for use in the preparation of cryoprecipitate and cryo-poorplasma.

For preparing cryoprecipitate and cryo-poor plasma, units were thawed ina temperature controlled 4° C. water bath, with a total thaw time ofapproximately 6 hr 30 minute for the large cryo units and 4 hr 30 minfor the single cryo units. The thawed units were centrifuged for 12minutes at 4° C. at 4200 rcf, with a slow deceleration. The cryo-poorsupernatants were removed from the cryoprecipitates by transferring outof the 1000 mL transfer bag, while maintaining a small amount of plasmafor re-suspension of the cryoprecipitates. Following resuspension, thecryoprecipitate units were frozen for storage at −30° C.

The frozen, stored cryoprecipitate units were thawed in a Helmer plasmathawer set at 35° C., with the cryoprecipitate full dissolved with novisible particulate matter. Thawed units were stored in a temperaturecontrolled cabinet at 22° C., with samples removed at defined intervalsof <2 hr, 6 hr, 24 hr and 5 days for analytical testing. Samples weretested for Factor VIII (FVIII) and Fibrinogen (FIB), with resulting datain Table 1.

TABLE 1 Fibrinogen and Factor VIII in cryoprecipitate preparations. 2 hr6 hr 24 hr 5 days Large volume (n = 4), 60.2 ± 4.9 mL Cryo FIB 492.7 ±70.7 498.7 ± 74.0 501.3 ± 61.46 482.9 ± 74.8 (mg) Cryo FIB 181.2 ± 24.3183.5 ± 26.6 184.4 ± 21.22 177.6 ± 26.7 (mg/unit*) Cryo FVIII 182.6 ±37.9 176.3 ± 26.9 177.6 ± 73.4  145.7 ± 37.5 (IU) Cryo FVIII  67.2 ±13.7 64.9 ± 9.6 65.2 ± 26.6  53.6 ± 13.5 (IU/unit*) Single unit (n = 2),24.1 ± 11.5 mL Cryo FIB 315.4 ± 49.1 315.5 ± 38.8 301.2 ± 35.4  274.2 ±55.3 (mg) Cryo FIB 192.6 ± 4.2  183.5 ± 26.6 184.4 ± 3.1  167.0 ± 11.4(mg/unit*) Cryo FVIII  94.5 ± 32.5  89.2 ± 40.0 82.4 ± 33.0  69.3 ± 40.0(IU) Cryo FVIII  57.0 ± 12.2  53.4 ± 17.3 49.5 ± 13.5  41.1 ± 19.0(IU/unit*) *Based on AABB unit volume of 200 mL

Example 2: Preparation of Pathogen Inactivated Cryoprecipitate andCryo-Poor Plasma

Multiple plasma units obtained from blood group A donors were pooled toobtain plasma preparations with volumes of about 650 mL each (e.g.,large volume). Pathogen inactivation and preparation of cryoprecipitateand cryo-poor plasma was undertaken with the pooled plasma units. Theplasma was subjected to photochemical pathogen inactivation using thecommercially available INTERCEPT Blood System for Plasma (CerusCorporation), to yield three individual pathogen-inactivated plasma (PIplasma) units from each pool. The three PI plasma units (3 containers,see e.g., 112, 114, and 116 in FIG. 1B) generated from each INTERCEPTprocessing set were combined by transferring into a sterile-docked,single 600 mL transfer bag (see e.g., 122 in FIG. 1B) and frozen at −30°C. for use in the preparation of cryoprecipitate and cryo-poor plasma.

For preparing cryoprecipitate and cryo-poor plasma, pooled units werethawed in a temperature controlled 4° C. water bath, with a total thawtime of approximately 6 hr 15 minutes. The thawed units were centrifugedfor 12 minutes at 4° C. at 4200 rcf, with a slow deceleration. Thecryo-poor plasma supernatants were removed from the cryoprecipitates bytransfer into the three previous containers, 60 mL of the plasma (i.e.,cryo-poor plasma) added back to the cryoprecipitate for re-suspension,and the cryoprecipitate units were frozen for storage at −30° C.

The frozen, stored cryoprecipitate units were thawed in a Helmer plasmathawing system at 37° C., with the cryoprecipitate fully dissolved withno visible particulate matter. Thawed units were stored in a temperaturecontrolled cabinet at 22° C., with samples removed at defined intervalsat least through day 5 post-thaw for analytical testing of Factor VIII(FVIII) and Fibrinogen (FIB), with resulting data in Table 2:

TABLE 2 Fibrinogen and Factor VIII in cryoprecipitate preparations. <2hr 6 hr 24 hr 48 hr Cryo FIB (mg) Cryo prep 1 960.5 926.5 942.0 937.8Cryo prep 2 661.4 676.0 670.0 683.3 Cryo FVIII (IU) Cryo prep 1 273.8277.6 277.9 188.1 Cryo prep 2 252.9 260.8 248.9 174.2

Example 3: Preparation of PI Cryoprecipitate and Cryo-Poor Plasma

Pathogen inactivated (PI) cryoprecipitate and cryo-poor plasmasupernatant were prepared as three large volume (647±2 mL) input poolsof 2-3 units of ABO matched whole blood derived plasma in CPDanticoagulant within 8 hr of draw.

The pooled plasma was subjected to photochemical pathogen inactivationusing amotosalen and UVA, with the commercially available INTERCEPTBlood System for Plasma. Baseline samples were collected prior toINTERCEPT treatment, and pathogen inactivation was performed accordingto the manufacturer's package insert. The three PI plasma units (3containers, see e.g., 112, 114, and 116 in FIG. 1B) generated from eachINTERCEPT processing set were combined by sealing above the connection,sterilely connecting a 600 mL transfer bag (see e.g., 122 in FIG. 1B),and transferring by gravity flow. After sampling, pathogen inactivatedplasma preparations were subjected to rapid freezing and stored at −30°C. for use in the preparation of cryoprecipitate.

For preparing cryoprecipitate, the frozen plasma was thawed in a 4° C.water bath within approximately 12 hr, and centrifuged at 4,000×g for 12min to sediment the cryoprecipitate. The cryo-poor plasma was removedusing a plasma expressor and transferred back into the three plasma bagsof the INTERCEPT processing set, leaving approximately 60 mL of theplasma (i.e., cryo-poor plasma) for resuspension of the cryoprecipitate.The cryoprecipitate bag and CPP bags were separated and sealed using atubing sealer, and frozen at −30° C. for storage.

For characterization, the frozen cryoprecipitate and cryosupernatantswere thawed at 37° C. in a QuickThaw™ Plasma Thawing System (Helmer,Noblesville, Ind.) and held at room temperature (22° C., 2 units) orrefrigerated (4° C., 1 unit) for sterile sampling at times 0 hr, 6 hr,24 hr, day 3 and day 5 post-thaw for analytical testing. In vitro assaysfor cryoprecipitate and cryo-poor plasma supernatant characterizationincluded total fibrinogen and Factor VIII, as measured on dilutedsamples, using an AMAX coagulation analyzer. Table 3 includes totalfibrinogen and Factor FVIII content for each of the threecryoprecipitate preparations.

TABLE 3 Fibrinogen and Factor VIII in cryoprecipitate preparations. 0 hr6 hr 24 hr D 3 D 5 Cryo FIB (mg) Cryo prep 1 (22° C.) 901 857 887 ND 887Cryo prep 2 (22° C.) 788 908 ND 771 995 Cryo prep 3 (4° C.) 772 896 969ND 907 Cryo FVIII (IU) Cryo prep 1 (22° C.) 278 319 280 ND 286 Cryo prep2 (22° C.) 319 347 ND 268 229 Cryo prep 3 (4° C.) 316 307 322 ND 218 ND:not determined.

Fibrinogen and Factor VIII were also determined for the cryo-poor plasmaby the same method. At time 0 hr, fibrinogen content was 772 mg, 746 mgand 736 mg total for preps 1, 2 and 3, respectively. Also, at time 0 hr,FVIII content was 54, 46 and 70 IU total for preps 1, 2 and 3,respectively. Thrombin generation activity was also determined bystandard methodologies and found to be at high levels.

Example 4: Preparation of PI Cryoprecipitate and Cryo-Poor Plasma

Pathogen inactivated (PI) cryoprecipitate and cryo-poor plasmasupernatant were prepared as large volume (585 to 650 mL) input of wholeblood derived FFP, whole blood derived PF24 or apheresis plasma(apheresis FFP) obtained from blood group A, B and/or O donors. Sixreplicates were prepared from pools of 5 to 6 iso-group units of wholeblood derived plasma collected in CP2D anticoagulant to yieldapproximately 1700 mL. The pooled plasma was split into two components(target 625 mL±25 mL, FFP and PF24) and stored at room temperature forup to 8 hr (FFP) or 24 hr (PF24) prior to subjecting the plasma tophotochemical pathogen inactivation using the commercially availableINTERCEPT Blood System, and freezing. Two units were maintained asuntreated controls without pathogen inactivation (target 215-235 mL, FFPand PF24). Additionally, six replicates of apheresis plasma werecollected in ACD anticoagulant from a maximum of two iso-group donorsand split into two components: one (target 625+25 mL) which was storedat room temperature for up to 8 hr prior to subjecting the plasma topathogen inactivation and freezing, and the other maintained asuntreated control. Baseline samples were collected prior to INTERCEPTtreatment, and pathogen inactivation was performed according to themanufacturer's package insert. The three PI plasma units (3 containers,see e.g., 112, 114, and 116 in FIG. 1B) generated from each INTERCEPTprocessing set were combined by transferring into a sterile-connected,single 800 mL transfer bag (Terumo) (see e.g., 122 in FIG. 1B) andfrozen for use in the preparation of cryoprecipitate. Controls werefrozen without pathogen inactivation treatment.

For preparing cryoprecipitate, the combined frozen plasma was thawed ina temperature controlled 2-6° C. refrigerator, with a total thaw time ofapproximately 24 hr. The thawed plasma was centrifuged to sediment thecryoprecipitate, and the cryo-poor plasma supernatants were removed fromthe cryoprecipitate using a plasma expressor and transferred into thethree previous containers, leaving sufficient plasma (i.e., thecryo-poor plasma) to result in about 60 mL of resuspendedcryoprecipitate, the cryoprecipitate bag then was separated from thethree cryo-poor plasma bags using a tube sealer, and the cryoprecipitateand CPP units frozen for storage.

For characterization, the frozen cryoprecipitate and CPPcryosupernatants were thawed at 37° C. in a QuickThaw™ Plasma ThawingSystem (Helmer, Noblesville, Ind.) and held at room temperature (20-24°C.) for sterile sampling at times 0, 24 and 120 hours post-thaw foranalytical testing. In vitro assays for cryoprecipitate and/or CPPcryosupernatant include a panel of coagulation parameters (e.g., PT,aPTT, thrombin generation), coagulation factors and hemostatic systemproteins (e.g., fibrinogen, Factors II, V, VII, VIII (VIII:C), IX, X,XI, XIII, vWF, ADAMTS-13), and other proteins and markers and/orfunction (e.g., antithrombin III, Protein C, Protein S, Alpha-2-PI,thrombin-antithrombin complexes, Factor VIIa, NAPTT, C3a, Ig's, ROTEM).

Analysis of FVIII, FXIII and fibrinogen was performed using an AMAXDestiny Plus coagulation analyzer and Stago Diagnostic reagents. Thefollowing Tables 4 and 5 include total fibrinogen and FVIII at times 0,24 and 120 hours post-thaw for containers of cryoprecipitate productprepared from whole blood derived FFP, whole blood derived PF24 andapheresis derived FFP, with ABO blood types as listed, and support anextended post-thaw expiry for cryoprecipitate as disclosed herein.

TABLE 4 Total fibrinogen content (mg) after post-thaw storage. PlasmaUnit t = 0 t = 24 hr t = 120 hr WBD FFP Group O Average 758 786 793 SD192.4 229.8 183.8 WBD FFP Group A Average 767 827 794 SD 91.0 52.7 81.6WBD FFP All groups Average 762 806 794 SD 134.7 150.8 127.2 PF24 Group OAverage 762 768 775 SD 150.5 183.1 196.7 PF24 Group A Average 693 682695 SD 77.0 97.3 64.5 PF24 All groups Average 728 725 735 SD 113.5 139.5138.1 Aph FFP Group O Average 923 914 963 SD 195.3 281.2 239.1 Aph FFPGroup A and B Average 954 1041 1052 SD 17.2 93.4 100.7 Aph FFP Allgroups Average 942 978 1008 SD 99.9 186.1 158.3

TABLE 5 Total Factor VIII content (IU) after post-thaw storage. PlasmaUnit t = 0 t = 24 hr t = 120 hr WBD FFP Group O Average 178 158 138 SD50.7 46.8 5.1 WBD FFP Group A Average 226 195 204 SD 30.7 34.9 45.5 WBDFFP All groups Average 202 176 171 SD 45.7 42.2 46.2 PF24 Group OAverage 197 175 168 SD 14.7 12.6 6.5 PF24 Group A Average 197 211 243 SD14.7 14.1 32.7 PF24 All groups Average 197 193 206 SD 13.2 23.3 45.9 AphFFP Group O Average 184 72 67 SD 52.4 16.8 18.8 Aph FFP Group A and BAverage 269 110 100 SD 65.9 48.8 29.0 Aph FFP All groups Average 235 9183 SD 70.8 37.0 27.6

Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI andFibrinogen content were determined for each of the six cryo-poor plasmasupernatants obtained from the apheresis derived FFP, with the followingaverage total content for the six samples: Factor V (464.4 IU; SD 38.1),Factor VII (465.4 IU; SD 55.4), Factor VIII (91.9 IU; SD 32.8), FactorIX (464.7 IU; SD 54.6), Factor X (494.8 IU; SD 10.7), Factor XI (507.8IU; SD 67.5), and Fibrinogen (975.7 mg; SD 107.6).

For additional CPP preparations, multiple whole blood derived plasmacollections were pooled and split into 625 mL components, and subjectedto photochemical pathogen inactivation using INTERCEPT Blood System forPlasma. In one study comparing two commercially available transfer bags,the three PI plasma units (3 containers, see e.g., 112, 114, and 116 inFIG. 1B) generated from each INTERCEPT processing set were combined bytransferring into a sterile-connected, single 750 mL or 800 mL transferbags (see e.g., 122 in FIG. 1B) and frozen at −30° C. for use in thepreparation of cryoprecipitate.

For preparing cryoprecipitate and CPP, the bags containing frozenpathogen-inactivated plasma were thawed in a 4° C. water bath forapproximately 5 hr. The thawed plasma was centrifuged to sediment thecryoprecipitate, and the cryo-poor plasma supernatants were removed fromthe cryoprecipitate and transferred back into two of the three previouscontainers (see e.g., bags 112 and 114 in FIG. 1B), leavingapproximately 100 mL of plasma (i.e., the cryo-poor plasma) to resuspendthe cryoprecipitate, which was then transferred back into the third ofthe three previous containers (see e.g., bag 116 in FIG. 1B), and thecryoprecipitate and CPP units were frozen for storage.

Subsequent analysis of fibrinogen and Factor VIII levels in thecryo-poor plasma indicated high levels of fibrinogen, but no significantdifferent between materials produced using either of the two transferbags.

Similarly, additional CPP preparations were prepared from multiple unitsof whole blood derived plasma that were pooled by combining into asterile connected 600 mL transfer bag, to obtain pooled plasmas with avolume of 585-650 mL. The pooled plasma was subjected to photochemicalpathogen inactivation using INTERCEPT Blood System for Plasma permanufacturer's instructions and as described above. The three resultingPI plasma units (3 containers, see e.g., 112, 114, and 116 in FIG. 1B)generated from each INTERCEPT processing set were combined bytransferring into a sterile-connected, single 600 mL transfer bag (seee.g., 122 in FIG. 1B), frozen in a blast freezer and transferred to astorage freezer at ≤−25° C. for use in the preparation ofcryoprecipitate.

For preparing cryoprecipitate and CPP, the bags containing frozenpathogen-inactivated plasma were thawed in a 2-6° C. refrigerator for20-24 hr, and centrifuged to sediment the cryoprecipitate. The cryo-poorplasma supernatants (˜550 mL) were removed from the cryoprecipitate andtransferred back into two of the three previous containers (see e.g.,bags 112 and 114 in FIG. 1B), leaving approximately 50 mL of plasma(i.e., the cryo-poor plasma) to resuspend the cryoprecipitate, which wasthen transferred back into the third of the three previous containers(see e.g., bag 116 in FIG. 1B). Approximately 50 mL of CPP wastransferred back into the 600 mL transfer bag to wash and collectresidual cryoprecipitate and then transferred into and combined with theinitial cryoprecipitate. This process yielded one container ofcryoprecipitate (˜100 mL) and two containers of cryo-poor plasma (˜250mL each). The CPP units and cryoprecipitate were frozen for storage.Analysis of five cryo-poor plasma preparations found a fibrinogencontent of 288±37 mg and a Factor VIII content of 42±14 IU.

Example 5: PI Cryoprecipitate from Two Cryo Preparations

Pathogen inactivated cryoprecipitate compositions of the presentdisclosure may be combined to yield a cryoprecipitate composition withhigher levels of desired factors, such as for example fibrinogen andFactor VIII. More specifically, a first cryoprecipitate is prepared froma large volume input of approximately 600 mL of FFP (e.g., 2-3 units,pooled) that is subjected to pathogen inactivation (e.g., INTERCEPTBlood System), as described in Example 2 above and illustrated in FIG.1B. Following sedimentation of the cryoprecipitate, the cryo-poorsupernatant is transferred back into the three containers for storage,leaving sufficient plasma for resuspension of the cryoprecipitate inapproximately 35 mL. In addition, a second cryoprecipitate is preparedfrom a large volume input of approximately 600 mL of FFP (e.g., 2-3units, pooled) of the same ABO type as the first cryoprecipitate andsubjected to pathogen inactivation treatment in a similar manner. Thecontainer with the second cryoprecipitate is separated from the threecryo-poor plasma bags using a tube sealer, prior to combining with thefirst cryoprecipitate (FIG. 1C). The second cryoprecipitate (labeledCryo “freeze” #2) is connected using a sterile connecting device to thecontainer with the first cryoprecipitate, which has also been separatedfrom its corresponding three cryo-poor plasma bags, and the twocryoprecipitate preparations combined by transfer prior to re-freezingor storage at room temperature for use.

Example 6: Pathogen-Inactivated Cryo-Poor Plasma for Guillain-BarréSyndrome

Pathogen-inactivated plasma compositions of the present disclosure maybe used for treatment of Guillain-Barré syndrome. More specifically, forexample, to evaluate the use of pathogen-inactivated cryo-poor plasma ofthe present disclosure in therapeutic plasma exchange for treatment ofGuillain-Barré syndrome, a randomized, double-blind clinical study isperformed, comparing pathogen-inactivated cryo-poor plasma andintravenous immunoglobulin. Study volunteers diagnosed are enrolledwithin two weeks of the start of symptoms at 100 subjects per group. Forthe pathogen-inactivated cryo-poor plasma treatment group, subjectsreceive multiple plasma exchanges (e.g., five) over a two week period,each as a 50 mL/kg exchange. For the IVIG treatment group, subjectsreceive five daily infusions of IVIG (e.g., GAMMAGARD, Baxter) at 0.4gm/kg body weight/day.

Subjects are monitored over a period of 12 months for clinical adverseevents and the following primary measure of efficacy: Proportion ofpatients with more than 1 grade improvement in Hughes Functional Grade(FG) at 28 days. Additional secondary measures of efficacy as measuredat 28 days and later points (e.g., 6 months) include days required for 1grade improvement of FG, days required for 2 grade improvement of FG,changes in activity of daily living (ADL), and one or more of handdynamometer, Visual Analog Pain Scale, McGill Pain Questionnaire-ShortForm, Neuromuscular Functional Assessment Index, Jebsen-Taylor HandFunction Test, Minnesota Rate of Manipulation and Manual DexterityTests, Walk Test and Center for Epidemiological Studies Depression Scale(CES-D).

Example 7: Pathogen-Inactivated Plasma for CIDP

Pathogen-inactivated plasma compositions of the present disclosure maybe used for treatment of chronic inflammatory demyelinatingpolyneuropathy (CIDP). More specifically, for example,pathogen-inactivated cryo-poor plasma compositions of the presentdisclosure are used in therapeutic plasma exchange for the treatment ofCIDP. Briefly, CIDP is a peripheral nerve disease of presumed autoimmuneetiology that may include both humoral and cell-mediated immuneresponses. CIDP patients receive ten plasma exchange treatments overfive weeks with 40-50 mL/kg plasma exchanged. Therapeutic response ismeasured by improvement or stabilization in neurological symptoms.Clinical outcomes are assessed during and after the treatment periodusing one or more of the Inflammatory Neuropathy Cause and Treatment(INCAT) score, maximum grip strength, the Medical Research Council (MRC)sum score, the Rasch-built Overall Disability Scale (R-ODS), and/orelectrophysiological evaluations (see e.g., Dyck, et al., 1994, Ann.Neurol. 3:838-845).

INCAT Score. The INCAT score and changes in the score from baseline aredetermined. The INCAT disability score ranges from 0 to 10 and is thesum of arm and leg disability each rated between 0 and 5 (where arm=0indicates ‘no upper limb problems’ and arm=5 indicates ‘inability to useeither arm for any purposeful movement’, and leg=0 indicates ‘walkingnot affected’, and leg=5 indicates ‘restricted to wheelchair, unable tostand and walk a few steps with help’). Thus, a higher INCAT disabilityscore indicates greater disability. Negative values for change in INCATscore indicate improvement, with a more negative value indicatinggreater improvement compared with the value at baseline. Improvement isdefined as an INCAT score decrease by at least 1 point.

Maximum Grip Strength. The mean maximum grip strength of the dominanthand and changes from baseline are determined. Positive values forchange in maximum grip strength indicate improvement. Improvement isdefined as improvement by at least 8 kPa.

Medical Research Council Sum Scale (MRC). The MRC sum score and changesfrom baseline are determined. The 80-point MRC sum score is the sum ofscores for eight bilateral (left and right side) muscle groups, eachrated between 0 (no visible contraction) to 5 (normal movement). Ahigher MRC sum score indicates greater muscle contraction/limb movement.Positive values for change in MRC sum score indicate improvement, with amore positive value indicating greater muscle contraction/limb movementcompared with the value at baseline.

Example 8: Pathogen-Inactivated Plasma for Renal Transplantation

Pathogen-inactivated plasma compositions of the present disclosure maybe used in conjunction with solid organ transplantation. For example,pathogen-inactivated cryo-poor plasma compositions are used for atherapeutic plasma exchange regimen in conjunction with ABO-incompatiblekidney transplantation to reduce circulating antibody (e.g., IgG) thatmay contribute to transplant rejection. More specifically, in oneexample, transplant patients receiving an ABO-incompatible kidney from aliving donor are subjected to a preconditioning regimen of multipletherapeutic plasma exchange (TPE) treatments before transplant to reduceABO antibody (e.g., anti-A, anti-B) titers to a desired level, such asfor example to pre-transplant titers of less than 16. TPE treatments areperformed daily prior to transplant using accepted plasma exchangemethods known in the art and as described herein, with the number of TPEtreatments based on the initial ABO antibody titers. For example, in oneembodiment, two TPE treatments are used for an initial antibody titer of16, three TPE treatments for an initial titer of 32, four TPE treatmentfor an initial titer of 64, five TPE treatments for an initial titer of128, seven TPE treatments for an initial titer of 256, nine TPEtreatments for an initial titer of 512, eleven TPE treatments for aninitial titer of 1024, and fifteen or more TPE treatment for an initialtiter of >1024. The pathogen-inactivated plasma compositions used forTPE treatment may be obtained from plasma donors seropositive forcytomegalovirus (CMV).

On the day of transplant, high risk patients may be subjected tosplenectomy and/or anti-CD20 therapy. Following the kidney transplantprocedure, the patients are subjected to one or more additional dailyTPE treatments (e.g., two, three) with the pathogen-inactivated plasmato reduce the risk of antibody rebound.

Example 9: Pathogen-Inactivated Plasma for Burn Resuscitation

Pathogen-inactivated plasma compositions of the present disclosure maybe used for fluid resuscitation in a subject suffering from burns (e.g.,burn shock resuscitation). More specifically, in one example, a subjectsuffering from major burns representing approximately 25% of total bodysurface area (TBSA) is infused with ABO-matched pathogen-inactivatedcryo-poor plasma prepared as described above. Infusion of the CPP isinitiated based on an amount calculated as 3 mL of CPP per kg bodyweight per % TBSA, with half of the amount infused within the first 8hours. Resuscitation with the cryo-poor plasma is continued as guided bytitration to maintain a urine output of about 1.0 ml/kg/hour.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents(especially in the context of the following claims) are to be construedto cover both the singular and the plural, unless otherwise indicatedherein or clearly contradicted by context. The terms “comprising,”“having,” “including,” and “containing” are to be construed asopen-ended terms (i.e., meaning “including, but not limited to,”) unlessotherwise noted. Wherever an open-ended term is used to describe afeature or element, it is specifically contemplated that a closed-endedterm can be used in place of the open-ended term without departing fromthe spirit and scope of the disclosure. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the descriptionand does not pose a limitation on the scope of the description unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe compositions, methods, and kits disclosed herein.

Preferred embodiments are described herein. Variations of thosepreferred embodiments may become apparent to those working in the artupon reading the foregoing description. It is expected that skilledartisans will be able to employ such variations as appropriate, and thepractice of the compositions, methods, and kits described hereinotherwise than as specifically described herein. Accordingly, thecompositions, methods, and kits described herein include allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the description unless otherwise indicatedherein or otherwise clearly contradicted by context.

LIST OF EMBODIMENTS

-   Embodiment 1. A method of treating a disease or condition indicated    for treatment by plasma exchange in a subject in need thereof,    comprising administering to the subject a therapeutically effective    amount of pathogen-inactivated plasma composition by plasma    exchange.-   Embodiment 2. The method of embodiment 1, wherein the disease or    condition is indicated for treatment with albumin by plasma    exchange.-   Embodiment 3. The method of embodiment 1 or embodiment 2, wherein    the disease or condition is Guillain-Barré syndrome, chronic    inflammatory demyelinating polyneuropathy, myasthenia gravis, a    paraproteinemic polyneuropathy, Goodpasture's syndrome, or    cryoglobulinemia.-   Embodiment 4. The method of embodiment 1 or embodiment 2, wherein    the disease or condition is other than thrombocytopenic purpura    (TTP) or hemolytic-uremic syndrome (HUS).-   Embodiment 5. The method of embodiment 1 or embodiment 2, wherein    the disease or condition is burn shock resuscitation.-   Embodiment 6. The method of any one of embodiments 1-5, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated frozen plasma.-   Embodiment 7. The method of embodiment 6, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated fresh frozen plasma.-   Embodiment 8. The method of any one of embodiments 1-5, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated cryo-poor plasma.-   Embodiment 9. The method of embodiment 8, wherein the disease or    condition is thrombocytopenic purpura (TTP) or hemolytic-uremic    syndrome (HUS).-   Embodiment 10. A method of treating a disease or condition indicated    for treatment by infusion with intravenous immunoglobulin in a    subject in need thereof, comprising administering to the subject a    therapeutically effective amount of pathogen-inactivated plasma    composition by plasma exchange.-   Embodiment 11. The method of embodiment 10, wherein the disease or    condition is Guillain-Barré syndrome, myasthenia gravis,    polymyositis, dermatomyositis, or chronic inflammatory demyelinating    polyneuropathy.-   Embodiment 12. The method of embodiment 10, wherein the disease or    condition is other than thrombocytopenic purpura (TTP) or    hemolytic-uremic syndrome (HUS).-   Embodiment 13. The method of any one of embodiments 10-12, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated frozen plasma.-   Embodiment 14. The method of embodiment 13, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated fresh frozen plasma.-   Embodiment 15. The method of any one of embodiments 10-12, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated cryo-poor plasma.-   Embodiment 16. The method of embodiment 15, wherein the disease or    condition is thrombocytopenic purpura (TTP) or hemolytic-uremic    syndrome (HUS).-   Embodiment 17. A method of treating a disease or condition selected    from the group consisting of Guillain-Barré syndrome, myasthenia    gravis, polymyositis, dermatomyositis and chronic inflammatory    demyelinating polyneuropathy in a subject, comprising administering    to a subject in need thereof a therapeutically effective amount of    pathogen-inactivated plasma composition by plasma exchange.-   Embodiment 18. The method of embodiment 17, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated frozen plasma.-   Embodiment 19. The method of embodiment 18, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated fresh frozen plasma.-   Embodiment 20. The method of embodiment 17, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated cryo-poor plasma.-   Embodiment 21. The method of any one of embodiments 1-20, wherein    the pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    thawing.-   Embodiment 22. The method of any one of embodiments 1-20, wherein    the pathogen-inactivated plasma composition is a lyophilized or    freeze-dried plasma composition.-   Embodiment 23. The method of embodiment 22, wherein the    pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    reconstitution.-   Embodiment 24. A method of treating thrombocytopenic purpura (TTP)    or hemolytic-uremic syndrome (HUS) in a subject, comprising    administering to a subject in need thereof a therapeutically    effective amount of a pathogen-inactivated plasma composition by    plasma exchange, wherein the pathogen-inactivated plasma composition    comprises pathogen-inactivated cryo-poor plasma.-   Embodiment 25. A method of treating a solid organ transplant    recipient to prevent an immune-mediated solid organ transplant    rejection, comprising administering to the transplant recipient a    therapeutically effective amount of a pathogen-inactivated plasma    composition by plasma exchange, wherein the plasma exchange is prior    to the transplant procedure.-   Embodiment 26. The method of embodiment 25, wherein the    immune-mediated transplant rejection is an antibody-mediated    transplant rejection.-   Embodiment 27. The method of embodiment 26, wherein the    antibody-mediated transplant rejection is an IgG-mediated transplant    rejection.-   Embodiment 28. The method of any one of embodiments 25-26, wherein    the solid organ transplant is an ABO-incompatible solid organ    transplant.-   Embodiment 29. The method of any one of embodiments 25-26, wherein    the solid organ transplant is an HLA-incompatible solid organ    transplant.-   Embodiment 30. The method of any one of embodiments 25-29, wherein    the solid organ transplant is a kidney transplant.-   Embodiment 31. The method of embodiment 30, wherein the kidney is    obtained from a living donor.-   Embodiment 32. The method of any one of embodiments 25-31, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated frozen plasma.-   Embodiment 33. The method of embodiment 32, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated fresh frozen plasma.-   Embodiment 34. The method of any one of embodiments 25-31, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated cryo-poor plasma.-   Embodiment 35. The method of any one of embodiments 25-34, wherein    the pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    thawing.-   Embodiment 36. The method of any one of embodiments 25-31, wherein    the pathogen-inactivated plasma composition is a lyophilized or    freeze-dried plasma composition.-   Embodiment 37. The method of embodiment 36, wherein the    pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    reconstitution.-   Embodiment 38. The method of any one of embodiments 1-37, wherein    the plasma exchange is achieved with a volume of the plasma    composition similar to the subject's plasma volume.-   Embodiment 39. The method of any one of embodiments 1-37, wherein    the plasma exchange is achieved with a volume of the plasma    composition between about 1 times and about 1.5 times the subject's    plasma volume.-   Embodiment 40. The method of any one of embodiments 1-37, wherein    the plasma exchange is achieved with a volume of the plasma    composition comprising about 40 mL/kg patient body weight.-   Embodiment 41. The method of any one of embodiments 1-37, wherein    the plasma exchange is achieved with a volume of the plasma    composition comprising about 60 mL/kg patient body weight.-   Embodiment 42. The method of any one of embodiments 1-41, wherein    the plasma exchange is performed at least two times.-   Embodiment 43. The method of embodiment 42, wherein the plasma    exchange is performed 2-5 times.-   Embodiment 44. The method of embodiment 42 or embodiment 43, wherein    the plasma exchange is performed 2-5 times within a period of two    weeks.-   Embodiment 45. The method of embodiment 42 or embodiment 43, wherein    the plasma exchange is performed 2-5 times within a period of one    week.-   Embodiment 46. The method of any one of embodiments 25-45, wherein    the plasma exchange is performed at least two times prior to the    transplant procedure.-   Embodiment 47. The method of embodiment 46, wherein the plasma    exchange is performed 2-15 times prior to the transplant procedure.-   Embodiment 48. The method of any one of embodiments 25-47, further    comprising administering to the transplant recipient a    therapeutically effective amount of pathogen-inactivated plasma    composition by plasma exchange after the transplant procedure.-   Embodiment 49. The method of embodiment 48, wherein the plasma    exchange is performed at least two times after the transplant    procedure.-   Embodiment 50. A method of fluid resuscitation in a subject    suffering from burns, comprising administering to a subject in need    thereof a therapeutically effective amount of a pathogen-inactivated    plasma composition.-   Embodiment 51. The method of embodiment 50, wherein the subject is    suffering from major burns comprising at least 20% of total body    surface area.-   Embodiment 52. The method of embodiment 50 or embodiment 51, wherein    the method of fluid resuscitation is a method of burn shock    resuscitation.-   Embodiment 53. The method of any one of embodiments 50-52, wherein    endothelial permeability, endothelial dysfunction and/or vascular    hyperpermeability is reduced by administration of the    pathogen-inactivated plasma composition.-   Embodiment 54. The method of any one of embodiments 50-53, wherein    administration of the pathogen-inactivated plasma composition    results in decreased subject mortality.-   Embodiment 55. The method of any one of embodiments 50-54, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated frozen plasma.-   Embodiment 56. The method of embodiment 55, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated fresh frozen plasma.-   Embodiment 57. The method of any one of embodiments 50-54, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated cryo-poor plasma.-   Embodiment 58. The method of any one of embodiments 50-57, wherein    the pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    thawing.-   Embodiment 59. The method of any one of embodiments 50-54, wherein    the pathogen-inactivated plasma composition is a lyophilized or    freeze-dried plasma composition.-   Embodiment 60. The method of embodiment 59, wherein the    pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    reconstitution.-   Embodiment 61. The method of any one of embodiments 50-60, wherein    about 1 mL to about 5 mL per kg body weight per % total burn surface    area (TBSA) of the pathogen-inactivated plasma composition is    administered to the subject.-   Embodiment 62. The method of any one of embodiments 50-60, wherein a    volume of the pathogen-inactivated plasma composition sufficient to    achieve an increase in blood pressure to at least about 50 mmHg is    administered to the subject.-   Embodiment 63. The method of embodiment 62, wherein a volume of the    pathogen-inactivated plasma composition sufficient to achieve an    increase in blood pressure to at least about 100 mmHg is    administered to the subject.-   Embodiment 64. The method of any one of embodiments 50-63, wherein    the pathogen-inactivated plasma composition is administered to the    subject within about 24 hours, within about 20 hours, within about    16 hours, within about 12 hours, within about 10 hours, within about    8 hours, within about 6 hours, within about 5 hours, within about 4    hours, within about 3 hours, within about 2 hours or within about 1    hours after the onset of burns or medical diagnosis thereof.-   Embodiment 65. The method of any one of embodiments 50-64, wherein    pathogen-inactivated plasma composition is administered to the    subject over a time period of about 24 hours.-   Embodiment 66. The method of embodiment 65, wherein    pathogen-inactivated plasma composition is administered to the    subject in multiple infusions over a time period of about 24 hours-   Embodiment 67. A method of treating a subject suffering from burns    or a trauma, the method comprising: administering to a subject in    need thereof a therapeutically effective amount of a    pathogen-inactivated plasma composition.-   Embodiment 68. The method of embodiment 67, wherein the subject is    suffering from burns.-   Embodiment 69. The method of embodiment 67, wherein the subject is    suffering from blunt trauma.-   Embodiment 70. The method of embodiment 67, wherein the subject is    suffering from penetrating trauma.-   Embodiment 71. The method of any one of embodiments 67-70, wherein    the subject is suffering from hemorrhage.-   Embodiment 72. The method of embodiment 71, wherein the subject is    suffering from internal hemorrhage.-   Embodiment 73. The method of any one of embodiments 67-72, wherein    the method is a method of fluid resuscitation.-   Embodiment 74. The method of any one of embodiments 67-73, wherein    the method reduces hemorrhage in the subject.-   Embodiment 75. The method of any one of embodiments 67-74, wherein    the method reduces hemorrhagic shock in the subject.-   Embodiment 76. The method of any one of embodiments 67-74, wherein    endothelial permeability is reduced in the subject.-   Embodiment 77. The method of any one of embodiments 67-74, wherein    the method reduces or prevents trauma-induced endotheliopathy in the    subject.-   Embodiment 78. The method of any one of embodiments 67-74, wherein    the method reduces or prevents traumatic coagulopathy in the    subject.-   Embodiment 79. The method of any one or embodiments 67-78, wherein    the infusion or treatment results in decreased subject mortality.-   Embodiment 80. A method of resuscitation from hemorrhagic shock in a    subject suffering from burns or a trauma, comprising administering    to the subject a therapeutically effective amount of a    pathogen-inactivated plasma composition.-   Embodiment 81. The method of embodiment 80, wherein the subject is    suffering from burns.-   Embodiment 82. The method of embodiment 80, wherein the subject is    suffering from blunt trauma.-   Embodiment 83. The method of embodiment 80, wherein the subject is    suffering from penetrating trauma.-   Embodiment 84. The method of any one of embodiments 80-83, wherein    the subject is suffering from internal hemorrhage.-   Embodiment 85. The method of any one of embodiments 80-84, wherein    the method reduces hemorrhage in the subject.-   Embodiment 86. The method of any one of embodiments 80-85, wherein    endothelial permeability is reduced in the subject.-   Embodiment 87. The method of any one of embodiments 80-85, wherein    the method reduces or prevents trauma-induced endotheliopathy in the    subject.-   Embodiment 88. The method of any one of embodiments 80-85, wherein    the method reduces or prevents traumatic coagulopathy in the    subject.-   Embodiment 89. The method of any one or embodiments 80-88, wherein    the treatment results in decreased subject mortality.-   Embodiment 90. The method of any one of embodiments 67-89, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated frozen plasma.-   Embodiment 91. The method of embodiment 90, wherein the    pathogen-inactivated plasma composition comprises    pathogen-inactivated fresh frozen plasma.-   Embodiment 92. The method of any one of embodiments 67-89, wherein    the pathogen-inactivated plasma composition comprises    pathogen-inactivated cryo-poor plasma.-   Embodiment 93. The method of any one of embodiments 67-92, wherein    the pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    thawing.-   Embodiment 94. The method of any one of embodiments 67-89, wherein    the pathogen-inactivated plasma composition is a lyophilized or    freeze-dried plasma composition.-   Embodiment 95. The method of embodiment 94, wherein the    pathogen-inactivated plasma composition is administered within 1    day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after    reconstitution.-   Embodiment 96. The method of any one of embodiments 67-95, wherein    the pathogen-inactivated plasma composition is first administered    less than 24 hours after the onset of trauma.-   Embodiment 97. The method of any one of embodiments 67-96, wherein    administration of the pathogen-inactivated plasma composition is    followed by administration of at least one additional intravenous    fluid.-   Embodiment 98. A method for preparing pathogen-inactivated cryo-poor    plasma, the method comprising:    -   a) photochemically inactivating one or more units of plasma in        the presence of a psoralen, wherein the photochemical        inactivation is performed under sterile conditions in a first        container containing the one or more units of plasma;    -   b) transferring under sterile conditions the one or more units        of plasma from the first container to a compound absorption        device (CAD) coupled to the first container;    -   c) transferring under sterile conditions the one or more units        of plasma from the CAD to two or more second containers coupled        to the CAD to provide pathogen-inactivated plasma;    -   d) transferring under sterile conditions the        pathogen-inactivated plasma from the two or more second        containers to a third container coupled to the two or more        second containers;    -   e) freezing the pathogen-inactivated plasma followed by thawing        of the pathogen-inactivated plasma under conditions that provide        for the formation of a cryoprecipitate and pathogen-inactivated        cryo-poor plasma;    -   f) transferring the pathogen-inactivated cryo-poor plasma to a        at least a first of the two or more second containers; and    -   g) transferring the cryoprecipitate to a second of the two or        more second containers.-   Embodiment 99. The method of embodiment 98, wherein at least a    portion of the pathogen-inactivated cryo-poor plasma is transferred    to each of at least two second containers in step f), and wherein    the cryoprecipitate is transferred to a third second container in    step g).-   Embodiment 100. The method of embodiment 98 or embodiment 99,    wherein, prior to step g), the cryoprecipitate is resuspended in    about 80 mL to about 120 mL of pathogen-inactivated cryo-poor    plasma.-   Embodiment 101. The method of embodiment 100, wherein, prior to step    g), the cryoprecipitate is resuspended in about 100 mL of    pathogen-inactivated cryo-poor plasma.-   Embodiment 102. A method for infusing pathogen-inactivated cryo-poor    plasma into a subject, comprising infusing into a subject in need    thereof a therapeutically effective amount of a pathogen-inactivated    cryo-poor plasma prepared by the method of any one of embodiments    98-101.-   Embodiment 103. The method of embodiment 102, wherein the subject is    suffering from one or more of burns, blunt trauma, penetrating    trauma, and hemorrhage.-   Embodiment 104. The method of embodiment 102 or embodiment 103,    wherein the infusion results in fluid resuscitation of the subject.-   Embodiment 105. The method of embodiment 102, wherein infusing the    pathogen-inactivated cryo-poor plasma into a subject is by    therapeutic plasma exchange.-   Embodiment 106. The method of embodiment 105, wherein the subject in    need thereof is a subject suffering from thrombocytopenic purpura    (TTP) or hemolytic-uremic syndrome (HUS).-   Embodiment 107. The method of any one of embodiments 102-106,    further comprising, prior to the infusion:    -   1) freezing the pathogen-inactivated cryo-poor plasma; and    -   2) thawing the pathogen-inactivated cryo-poor plasma.-   Embodiment 108. The method of embodiment 107, wherein the    pathogen-inactivated cryo-poor plasma is infused into the subject    within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days    after thawing.

1. A method of treating a disease or condition indicated for treatment by plasma exchange in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pathogen-inactivated plasma composition by plasma exchange, wherein the pathogen-inactivated plasma composition comprises pathogen-inactivated cryo-poor plasma.
 2. The method of claim 1, wherein the disease or condition is indicated for treatment with albumin by plasma exchange.
 3. The method of claim 1, wherein the disease or condition is other than thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). 4-5. (canceled)
 6. The method of claim 1, wherein the disease or condition is thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). 7-10. (canceled)
 11. The method of claim 1, wherein the pathogen-inactivated plasma composition is administered within 5 days after thawing.
 12. The method of claim 1, wherein the pathogen-inactivated plasma composition is a lyophilized or freeze-dried plasma composition. 13-66. (canceled)
 67. The method of claim 1, wherein the plasma exchange is achieved with a volume of the plasma composition between about 1 times and about 1.5 times the subject's plasma volume.
 68. The method of claim 1, wherein the plasma exchange is achieved with a volume of the plasma composition comprising about 30 mL/kg, about 40 mL/kg, about 50 mL/kg, or about 60 mL/kg patient body weight.
 69. The method of claim 1, wherein the plasma exchange is performed at least two times.
 70. The method of claim 69, wherein the plasma exchange is performed 2-5 times.
 71. The method of claim 69, wherein the plasma exchange is performed 2-5 times within a period of two weeks.
 72. The method of claim 1, wherein the pathogen-inactivated plasma composition comprises pathogen-inactivated cryo-poor plasma prepared from one or more units of plasma from whole blood donation.
 73. The method of claim 1, wherein the pathogen-inactivated plasma composition comprises pathogen-inactivated cryo-poor plasma prepared from one or more plasma units from apheresis collected plasma.
 74. The method of claim 1, wherein the pathogen-inactivated plasma composition comprises pathogen-inactivated cryo-poor plasma prepared from one or more units of plasma that are subjected to pathogen inactivation within 24 hours of donation.
 75. The method of claim 1, wherein the pathogen-inactivated plasma composition comprises pathogen-inactivated cryo-poor plasma prepared from multiple plasma units.
 76. The method of claim 1, wherein the pathogen-inactivated cryo-poor plasma is prepared from plasma that is pathogen-inactivated by photochemical inactivation.
 77. The method of claim 1, wherein the pathogen-inactivated cryo-poor plasma is prepared from plasma that is pathogen-inactivated with a psoralen. 